Organics doi: 10.3390/org7030039

Authors: Anastasia Golovina Fedor Antipin Vitaly Osyanin Dmitry Osipov Daniil Yakovlev Olga Terina Roman Ivanov

The increasing prevalence of antimicrobial resistance has stimulated interest in non-antibiotic small molecules that can restore or potentiate the activity of established antibacterial agents. In this study, a focused series of low-molecular-weight chromene derivatives was synthesized, structurally characterized, and evaluated primarily as antibacterial adjuvants rather than as stand-alone antibiotics. The experimental strategy was designed to distinguish intrinsic antibacterial activity from potentiating activity in combination with a partner antibiotic. Initial susceptibility testing was followed by combination experiments in selected bacterial strains, with particular emphasis on changes in the minimum inhibitory concentration (MIC) of meropenem or doripenem in the presence of each test compound. Broth microdilution combination assays demonstrated that compound 3a significantly reduced the MIC of meropenem and doripenem against methicillin-resistant Staphylococcus aureus (MRSA). The observed adjuvant effect suggests that chromene scaffolds may serve as promising candidates for the development of next-generation β-lactam enhancers aimed at overcoming carbapenem resistance.

Organics doi: 10.3390/org7030038

Authors: Theophilus Bhatti Ji-Yeong Bae

East Asian crowberry has been reported under Empetrum nigrum var. japonicum and E. nigrum subsp. asiaticum. This critical narrative review evaluates taxonomy, phytochemistry, and pharmacological evidence from Korean, Japanese, and Chinese source-reported material in the context of the wider Empetrum literature. Reassessment of primary reports identified a broader East Asian chemical evidence base than previously summarized, including methylated, methoxylated, and hydroxylated chalcone/dihydrochalcone derivatives, bibenzyls, triterpenoids, flavonoids, and related constituents. These reports raise the possibility of East Asian chemotypic differentiation, but direct comparative metabolomics using authenticated populations and standardized methods has not established their geographic specificity or abundance. Reported pharmacological activities include antioxidant and cytoprotective effects, nitric oxide and α-glucosidase inhibition, cancer cell cytotoxicity, anti-angiogenic activity in an in ovo chorioallantoic membrane model, and limited mammalian in vivo evidence, including a Korean carbon tetrachloride-induced hepatotoxicity model and a Chinese alcoholic fatty liver rat model. Evidence strength varies substantially because botanical authentication, extract standardization, dose–response reporting, and independent replication are inconsistent. The available literature therefore provides preliminary evidence consistent with potential East Asian chemotypic differentiation but does not establish a discrete chemotypic boundary. Priority needs are taxonomic authentication, harmonized chemical profiling, quantitative marker validation, extract standardization, compound-level testing, and independent pharmacological replication.

Organics doi: 10.3390/org7030037

Authors: Alexander V. Uvarov Evgenii V. Plotnikov Daria D. Eskova Evgeniy H. Sadykov Andrei S. Potapov Anastasia R. Kovrizhina Andrei I. Khlebnikov

Indolo[2,3-b]quinoxalines and their N-substituted derivatives exhibit anticancer activity. In this work, a convenient two-step protocol comprising base-promoted aldol condensation followed by oximation was used for the synthesis of novel β-hydroxy oximes from heterocyclic ketones. The oximes were obtained as Z/E mixtures with one isomer predominating, and DFT calculations confirmed the E-configuration as thermodynamically preferred by 1.0–1.4 kcal/mol. High isomerization barriers (49–56 kcal/mol) via nitrogen inversion indicate kinetic stability of the β-hydroxy oximes at room temperature. The tryptanthrin-based β-hydroxyketone 5 (6-hydroxy-6-(2-oxopropyl)indolo[2,1-b]quinazolin-12(6H)-one) proved most potent, with IC50 values of 58 µM (MCF-7), 59 µM (PC-3) and 135 µM (SKOV-3); its derivative 6-hydroxy-6-(2-(hydroxyimino)propyl)indolo[2,1-b]quinazolin-12(6H)-one oxime (compound 8) was less effective, while other derivatives were inactive or showed only weak effects. MCF-7 and PC-3 cells were more sensitive than SKOV-3 cells. Hence, compounds 5 and 8 are promising leads for further SAR optimization and anti-cancer evaluation.

Organics doi: 10.3390/org7030036

Authors: Priyanka R. Sakhare Amit Kumar Jha Praveen Kumar Vittal Seema Subba Rao Cheekatla

The development of sustainable and efficient methods for carbon–carbon (C–C) bond formation remains the main objective in modern organic synthesis. In recent years, photocatalysis has developed as a suitable alternative to conventional transition-metal-catalyzed approaches, offering mild reaction conditions, high functional-group tolerance, excellent atom economy, and the ability to utilize visible light as a clean and renewable energy source. Through unique radical-mediated pathways, photocatalytic strategies allow the selective activation of traditionally unreactive substrates, including haloarenes, alkanes, alcohols, carboxylic acids, and amines, thereby providing efficient routes to complex molecular architectures. Beyond organic synthesis, photocatalysis has also demonstrated significant potential in broader areas of applied chemistry. This review summarizes the major advances in photocatalytic C–C bond coupling reported from 2023 to early 2026, with special focus on C(sp3)–C(sp3), C(sp3)–C(sp2), and C(sp2)–C(sp2) bond-forming reactions. Representative catalytic systems, substrate scope, reaction mechanisms, and synthetic applications are critically discussed, including dual photoredox/transition-metal catalysis, metal-free photocatalysis, hydrogen atom transfer (HAT), proton-coupled electron transfer (PCET), radical–radical coupling, decarboxylative and deaminative functionalization, and enantioselective transformations. Finally, current challenges, emerging trends, and future opportunities for developing more sustainable, scalable, and selective photocatalytic C–C bond-forming methodologies are highlighted, providing a comprehensive resource for researchers working in synthetic and medicinal chemistry.

Organics doi: 10.3390/org7030035

Authors: Lili Cai Jiajun Chen Suimei Wei Suya Huang Yong-Guang Jia

Active molecules derived from traditional Chinese medicine (TCM) represent a valuable source of lead compounds for modern drug discovery, demonstrating considerable potential in the prevention and treatment of chronic diseases, cancer therapy, and immune modulation. Nevertheless, their clinical translation is often impeded by intrinsic limitations such as poor aqueous solubility, low bioavailability, inadequate chemical stability, and significant gastrointestinal irritation. Cyclodextrins (CDs) and their derivatives, characterized by a hydrophobic internal cavity, are capable of forming inclusion complexes with TCM and their derived active constituents, thereby improving their physicochemical and pharmacokinetic profiles. Over the past five years, substantial progress has been made in this domain. CD-based inclusion strategies have been shown to markedly enhance the solubility and dissolution rate of poorly water-soluble TCM compounds, including flavonoids, alkaloids, and terpenoids. Moreover, this approach contributes to improved drug stability, effective taste masking, and the achievement of modified release profiles, such as sustained or targeted delivery, ultimately leading to enhanced therapeutic efficacy and reduced adverse effects. The development of novel CD derivatives and smart delivery systems has further broadened their application potential. This review summarizes recent advances in the CD-based encapsulation of TCM active molecules, highlighting key formulation strategies that address persistent challenges in the modernization of TCM. It also provides a foundation for future research and development in natural product-based therapeutics.

Organics doi: 10.3390/org7030034

Authors: Aiyun Liu Youpeng Wang Ruihan Wang Redili Abulimiti Xiangru Hao Yunlei Wang Xiaoran Tian Huaiyuan Zhang Tonglin Wang Zhensheng Fu Wenxiu Zheng Junqiang Shi

Fluorinated isoquinoline-1,3-diones possess important biological activities and application value in many fields such as medicine, pesticides, and organic synthesis. This review summarizes the synthetic methods of fluorinated isoquinoline-1,3-diones reported in recent years, mainly including classical synthetic methods, visible-light-induced catalytic methods, and electroorganic synthesis. The mechanisms of each reaction are described. Among them, visible-light-induced and electrochemical approaches show improved sustainability and mild reaction conditions. In this review, these synthetic methods are summarized to provide a reference for the design and research of these compounds. Future perspectives on method development are also briefly considered.

Organics doi: 10.3390/org7030033

Authors: Oscar A. Douglas-Gallardo Valentino Cárdenas-Toledo Marta Navarro Enrique Francés-Poveda Jesús Naranjo Genesys L. Mahecha Felipe de la Cruz-Martínez Francisca Werlinger Agustín Lara-Sánchez Javier Martínez

The consistent increase in atmospheric CO2 concentration, mostly driven by the global combustion of fossil fuels, is considered one of the primary contributors to the increasing severity of environmental problems, like climate change and global warming. Attending to this issue requires innovative strategies that transform CO2 into a valuable resource. In this work, we report a sustainable and fully metal-free approach for the synthesis of cyclic carbonates via the direct coupling of CO2 with epoxides, using natural sugars as readily available, non-toxic organocatalysts in combination with tetrabutylammonium iodide (TBAI) as a cocatalyst. Seven representative mono- and disaccharides were screened, employing styrene oxide as a model substrate under mild reaction conditions (80 °C, 20 bar CO2, 2 h). Among them, D-xylose exhibited the best catalytic performance. The robustness of this catalytic system was further demonstrated through the efficient transformation of a wide range of terminal, internal, and biomass-derived epoxides into their corresponding cyclic carbonates with high yields and selectivity (up to 99%). Additionally, a set of computational simulations based on density functional theory (DFT) calculations was carried out to gain insight into the atomistic mechanisms involved in this chemical transformation. We identified that the hydroxyl groups of the sugar catalyst play a pivotal role in activating the epoxy ring-opening process, leading to cyclic carbonate formation. This bio-inspired strategy provides a green, cost-effective, and scalable pathway to produce key precursors for organic chemistry, contributing to the development of a circular carbon economy and the advancement of sustainable chemistry.

Organics doi: 10.3390/org7030032

Authors: Fengchun Liang Fuchong Li Penghua Yan Yuting Li Gaiguo Liu Youjie Li Baili Wang Huaqiang Zhang Yamin Zhang

Flexible organic solar cells (FOSCs) are a promising green energy technology due to their mechanical flexibility, light weight, low cost, and compatibility with large-area solution processing. Although the power conversion efficiency (PCE) of rigid organic solar cells has exceeded 20%, a significant performance gap remains for flexible devices, primarily constrained by the limitations of two key components: the flexible substrate and the transparent electrode. This review systematically summarizes recent research progress on flexible substrates, including ultrathin glass, polymer substrates, stretchable substrates, and bio-based substrates, and flexible transparent electrodes, including ITO, conductive polymers, carbon-based nanomaterials, ultrathin metal films, metal grids, and metal nanowire networks. Building on this, the review explores strategies for the synergistic design of substrates and electrodes, analyzing critical pathways for their co-optimization across four dimensions: interface engineering, mechanical compatibility, optical coupling, and process integration. Examining representative case studies from the literature, optimal substrate–electrode pairings for different application scenarios are summarized. Finally, the review outlines a future perspective on the evolution from compatibility toward functional integration, offering a systematic framework for the development of next-generation flexible photovoltaic devices that are efficient, stable, and adaptable to diverse application requirements.

Organics doi: 10.3390/org7030031

Authors: Md. Shamim Alam Mashud Ahmed Abdul Barik Samia Jahan Tofa Md. Koushic Uddin Antonio Greco Mohammad Mahbubul Alam Muksit Ahamed Chowdhury

Due to the rapid development of the textile industry and increased consumption of various textiles composed of both synthetic and natural fibers, large amounts of textile waste are produced, leading to environmental and economic problems on a global scale. Turning textile waste into carbon materials that can be used in a broad range of applications has become a viable solution to address this challenge in terms of sustainability and value generation. Natural and synthetic textile fibers have distinctive molecular structures with relatively high carbon content and variable chemical functionality; therefore, they have been identified as highly promising precursors for fabricating carbon materials with various electrochemical and environmental applications. At the same time, the properties of carbonized and activated textile fibers are strongly dependent on the molecular transformations taking place during thermal treatment and functionalization of textile fibers. This review will provide a comprehensive overview of the molecular evolution of natural and synthetic textile fibers during carbonization and activation processes in terms of dehydration, depolymerization, aromatization, heteroatom preservation, and graphitization mechanisms. The effect of precursor chemical composition, pyrolysis conditions, activation process, and heteroatom incorporation on the structure of carbonized and activated textile fibers and their physical and electrochemical properties will be analyzed. Particular emphasis is placed on electrochemical applications, including capacitive deionization, supercapacitors, electrocatalysis, and emerging smart electrochemical textile systems, highlighting how molecular transformation, pore engineering, and surface chemistry govern charge storage, ion adsorption, and catalytic behavior. In addition, major characterization techniques such as Raman spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Brunauer–Emmett–Teller surface area analysis will be reviewed and discussed in relation to understanding the interdependence between molecular structure and material properties. Finally, recent issues related to feedstock heterogeneity, scalability, energy efficiency, and sustainability of processing are highlighted, and future perspectives on multifunctional carbon structures and circular utilization of textile waste are discussed.

Organics doi: 10.3390/org7030030

Authors: Mukund Jha Amitabh Jha

Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most lethal malignancies, characterized by late diagnosis, aggressive local invasion, profound therapy resistance, and a suppressive tumor microenvironment. Currently known chemotherapy regimens for the treatment of PDAC are limited and typically depend on the stage of disease. For pre-surgery and post-surgery settings, modified combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin are used. Gemcitabine/nab-paclitaxel is an alternative regimen used for the disease at advanced stage. However, modest efficacy and high toxicity are often associated with these treatments. Therefore, more efficacious, safer, and novel therapeutic options are urgently required. The natural product curcumin has been shown to exert promising anti-inflammatory, pro-apoptotic, and antimetastatic activities in PDAC models. Inspired by these initial reports, there has been a sustained effort in the medicinal chemistry community to develop chemotherapeutic agents for the treatment of PDAC based on the chemical architecture of curcumin. This review highlights recent developments of multiple classes of curcumin analogs as a credible and versatile class of investigational agents for addressing the unmet therapeutic needs of pancreatic cancer.

Organics doi: 10.3390/org7030029

Authors: Heidi A. Dahlmann Finn Beruldsen Hayden L. Criswell Phillip F. Crook Evan C. Glassford Alyssa K. Jones Reece B. Mitchell Laura F. Mortan Nicholas Ryan Alexandria M. Smith Evan M. Vazquez

Ring-closing carbonyl-olefin metathesis (COM) reactions provide a straightforward method for producing cyclic alkenes from precursors containing carbonyl functional groups tethered to nucleophilic alkenes. Within the last decade, many methods for carrying out Lewis acid- or organocatalyzed COM reactions were reported; however, Brønsted–Lowry acid-catalyzed COM reactions are less developed. Herein, we report that phosphoric acid derivatives and N-triflylphosphoramides mediate COM reactions, although the substrate scope is limited to biaryl compounds that cyclize to produce phenanthrene products. We also disclose the synthesis and characterization of a previously non-fully characterized phosphoric acid derivative and a novel phosphoramide.

Organics doi: 10.3390/org7030028

Authors: Shweta K. Gediya Martin Wills

We have prepared two novel tethered (arene)Ru(II)/TsDPEN complexes, one containing a p-OTBS on the η6-arene ring, and the other with a p-CO2Et group at the same position, representing an electron-rich and electron-poor derivative. These have been evaluated in asymmetric transfer hydrogenation (ATH) of acetophenone derivatives and acetylcyclohexane. Both catalysts were effective in ATH and gave alcohols in high ees in most cases (with the exception of acetylcyclohexane reduction), mirroring results previously obtained using Ru(II) tethered catalysts. It was notable that the p-CO2Et-containing catalyst was more active than the untethered equivalent catalyst containing an ester on the η6-arene ring, although it still gave products of high ee. This indicates that N-η6-arene ring tethering can compensate for the lower activity of the electron-withdrawing ester group and may be a useful factor to consider for future catalyst design.

Organics doi: 10.3390/org7030027

Authors: Zeping Wang Shoko Ishikawa Yuki Fukuda Sayaka Yamada Meika Inomoto Desita Triana Aziz Xueyu Yang Zetry Puteri Tachrim Takeyuki Suzuki Yuta Murai Makoto Hashimoto

Phenylglycine (Phg) is a nonproteinogenic α-amino acid found in various bioactive molecules. The C-terminal activation of N-acyl Phg is often accompanied by oxazolone-mediated racemization, arising from the direct attachment of the phenyl ring to the α-carbon. After peptide bond formation with another chiral amino acid, this stereochemical erosion is observed as Phg-site epimerization and diastereomer formation. N-acyl activated esters, particularly N-hydroxysuccinimide (OSu) esters, are widely used for peptide bond formation with proteinogenic α-amino acids. Our previous study on N-trifluoroacetyl phenylglycine (TFA-Phg-OH) revealed that Phg-site epimer formation could still occur when TFA-Phg-OSu was employed as an acyl donor for coupling with amino acid ester hydrochlorides (AA–OMe·HCl) in the presence of a soluble organic base. To address these issues, in this study, we report a base-limited one-pot coupling of TFA-Phg-OH with α-amino acid ester hydrochlorides (AA–OR·HCl; R = Me or tert-Bu) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl), which effectively suppresses Phg epimerization. The resulting TFA-Phg–AA–OR dipeptides (AA = Ala, Val, Leu, Met, Phg) were all obtained at a >60% yield with a diastereomeric excess (de) ≥ 98.5%. Notably, reducing the amount of triethylamine further minimized epimer formation, while Ba(OH)2·8H2O and trifluoroacetic acid enabled stereoretentive deprotection of the N-TFA group and tert-butyl ester, respectively. This workflow provides practical access to both protected and deprotected Phg–AA motifs, thereby facilitating the preparation of unprotected Phg-containing peptide building blocks.

Organics doi: 10.3390/org7020026

Authors: Anastasia R. Kovrizhina Andrei I. Khlebnikov

Ninhydrins represent a promising chemical space for the search for new biologically active molecules with antimicrobial, antiprotease, and antitumor properties. In the present work, new ninhydrin derivatives were synthesized, and for the first time, a systematic in silico study of ninhydrins as multitarget ligands for five pharmacologically significant targets (HER1/HER4, HER2/HER3, Trk-B, PPAR-α, and LTβR) was conducted, whose amplification or overexpression plays a key role in the pathogenesis and progression of certain aggressive cancer types. Among the studied ninhydrin derivatives, compound 1 (2,2-dihydroxy-5,6-dimethoxy-1H-indene-1,3(2H)-dione) stands out as the most potentially active molecule. It exhibits high affinity for HER1/HER4, Trk-B, and PPAR-α, opening up potential applications in oncology (HER family and Trk-B inhibition during BDNF overexpression), neurodegenerative diseases (Trk-B modulation), and metabolic disorders (PPAR-α activation). Compound 4 (2,2-Dihydroxy-5-trifluoromethylindane-1,3-dione) is a leader in LTβR binding and also holds promise for immuno-oncology and anti-inflammatory strategies.

Organics doi: 10.3390/org7020025

Authors: Shai Ben Sasson Noa Naama Mikhail Kozlov Ibrahim Amer Moshe Portnoy

Our recent studies demonstrated that dialkylaminopyridine organocatalysts featuring an extensive secondary sphere preferentially phosphorylate the alcohol at the apolar domain of a model amphiphilic diol. In the present study, this site-selective behavior was corroborated across a broader range of amphiphilic diols. Furthermore, we found that the site selectivity can be inverted by applying certain saturated aliphatic amine bases in stoichiometric amounts. Screening identified cis-2,6-dimethylpiperidine as the most selective promoter, consistently inducing phosphorylation at the polar domain across all tested diols. Remarkably, despite being a secondary amine, this base did not produce any detectable phosphoramidate byproduct.

Organics doi: 10.3390/org7020024

Authors: Xiumei Bai Danila R. Chernyavskiy Anna D. Maksimova Ilya A. Yakushev Viktor A. Tafeenko Elena K. Beloglazkina Alexander V. Finko

We report the synthesis and single-crystal X-ray structures of three novel (Z)-5-arylidene-3-phenylrhodanine derivatives, differing in the substituents on the benzylidene fragment (two methoxy groups (compound I), a dioxine ring (compound II), or a dioxole ring (compound III)). Despite the overall similarity of the molecules, their supramolecular architectures were found out to be strikingly different. The results of intermolecular interactions in those structures are investigated via Hirshfeld surface, molecular electrostatic potential surface and non-covalent interaction analyses. The fine modulation of the arylidene substituent can switch the primary intermolecular synthon from weak S···S bonding to n···π* interactions, offering new possibilities for crystal engineering of rhodanine-based materials.

Organics doi: 10.3390/org7020023

Authors: Toshihiko Matsuura Airi Nakajima

Conventional oxidative hair dyes rely on aromatic amines, raising concerns about human health and environmental safety. This study reports a natural hair-coloring system using size-controlled ink particles (SIPs, ~170 nm in diameter) from cuttlefish ink and chitosan. Because both SIPs and hair surfaces carry negative charges near neutral pH, original SIPs exhibited poor deposition onto hair. Polyelectrolyte complexation with chitosan reversed the SIP surface charge under acidic conditions (maximum ζ ≈ +41 mV at pH 2.4), enabling electrostatic deposition onto hair fibers. Dynamic light scattering (DLS) revealed pH-responsive aggregation at pH 1.6–1.8 and redispersion at pH 2.8–4.3, while ultraviolet–visible (UV–Vis) spectra confirmed that the broadband absorption of melanin was preserved, consistent with predominantly noncovalent interactions. Scanning electron microscopy (SEM) showed a particle-based composite coating on hair fibers. An optimal SIP:chitosan weight ratio of 10:1 at pH ~4.7 yielded the darkest and most uniform coloration (L* = 32.89, ΔE*ab = 55.89) without metallic mordants, achieving darker coloration than representative plant-based natural colorants reported in the literature. These results demonstrate a marine-biomass-derived approach to natural black hair coloration with strong darkening performance.

Organics doi: 10.3390/org7020022

Authors: Ayumu Natsubori Momoka Ikeda Yushin Hosokawa Mizuki Akagawa Yoshikazu Horino

1,2,4-Trisubstituted chiral homoallylic alcohols are valuable intermediates in natural product synthesis and complex molecular architectures; however, their catalytic asymmetric synthesis remains challenging due to the need for precise control of regioselectivity, diastereoselectivity, E/Z geometry, and enantioselectivity. Herein, we report a palladium-catalyzed enantiospecific three-component reaction of aldehydes, borylated allyl acetates, and dimethylzinc for the efficient synthesis of 1,2,4-trisubstituted anti-(Z)-homoallylic alcohols. The present method employs readily accessible chiral borylated allyl acetates and proceeds with high levels of stereochemical control, providing a practical approach to structurally complex homoallylic alcohols.

Organics doi: 10.3390/org7020021

Authors: Andrea Navarrete-Mosquera Juan Pedro Palomares-Báez Rody Soto-Rojo Tomás Delgado-Montiel Samuel Soto-Acosta Nora Aydee Sánchez-Bojorge Daniel Glossman-Mitnik Jesús Baldenebro-López

This study presents a theoretical investigation of the adsorption and electronic structure of two imidazole derivatives, 4-(1,4,5-triphenylimidazol-2-yl)-aniline (M1) and N,N-dimethyl-4-(1,4,5-triphenylimidazol-2-yl)-aniline (M2), on an Fe(100) surface. A combined computational approach, employing Density Functional Theory for molecular reactivity, Density-Functional Tight-Binding for surface interactions, and Molecular Dynamics (MD) simulations for binding stability, was utilized to provide a comprehensive analysis. Quantum–chemical calculations indicate that both inhibitors exhibit strong donor characteristics, with M2 consistently demonstrating greater potential. This enhanced performance is attributed to the strong electron-donating nature and increased structural planarity conferred by the dimethylamine group in M2, which results in a lower HOMO-LUMO energy gap and higher chemical reactivity. Analysis of the inhibitor-surface interaction confirmed a strong electron donor-acceptor mechanism, indicative of stable chemical bond formation and a predominant chemisorption process. MD simulations revealed that both molecules form stable adsorption layers on the iron surface, suggesting initial adsorption behavior.

Organics doi: 10.3390/org7020020

Authors: Juozas Kiltinavičius Kristina Kantminienė Ilona Jonuškienė Ingrida Tumosienė

Reaction of 5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide with selected aldehydes and ketone provided novel hydrazone derivatives bearing azole moieties: pyrazole, pyrrole, and indole. The drug likeness of the newly synthesized compounds and their physicochemical characteristics were examined to fit Lipinski’s Rule of Five. N-(2,5-dimethyl-1H-pyrrol-1-yl)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carboxamide (5) exhibited the most favorable overall ADMET profile, combining compliance with key physicochemical requirements for antimicrobial activity with superior solubility and reduced predicted hepatotoxicity and nephrotoxicity. Despite generally elevated plasma protein binding across the series, this compound provided the most advantageous balance between permeability, systemic exposure, and safety.

Organics doi: 10.3390/org7020019

Authors: Suzana Apostolov Dragana Mekić Gorana Mrđan Gyöngyi Vastag

Thiocarbohydrazone derivatives represent a highly significant class in medicinal chemistry, characterized by a versatile scaffold defined with a thiocarbonyl (C=S) core and one or two imine (–C=N–) functionalities, allowing for precise modulation of their physicochemical and biological properties. The biological potential of a series of novel bis-substituted thiocarbohydrazone derivatives was predicted and evaluated through comprehensive in silico analysis. All investigated compounds complied with Lipinski’s Rule of 5, with most also satisfying the Rule of 3 while simultaneously exhibiting favorable pharmacokinetic properties and low predicted ecotoxicity. To substantiate these findings and elucidate the influence of para-substituents, chromatographic behavior of the studied derivatives was evaluated using reversed-phase thin-layer chromatography (RP-TLC). Initial linear regression analysis revealed statistically significant correlations between chromatographic parameters and in silico-derived descriptors of lipophilicity, pharmacokinetics, and ecotoxicity. Furthermore, cluster analysis and principal component analysis provided a robust and unambiguous interpretation of the structure–property relationships, highlighting substituent polarity as the leading factor controlling the bioactivity of bis-substituted thiocarbohydrazones, although the contribution of electronic effects cannot be neglected. Moreover, RM0 correlates with lipophilicity and pharmacokinetics, whereas m reflects ecotoxicity. Collectively, these findings emphasize the critical role of subtle structural variations in shaping the overall properties of these novel derivatives.

Organics doi: 10.3390/org7020018

Authors: Fumihiro Kawagoe Hiroya Tabuchi Taiyo Ideguchi Yuki Okamoto Souma Murata Tomofumi Yatsu Syota Yamada Kaori Yasuda Yusuke Akagi Masashi Takano Toshie Fujishima Yoshiki Miyata Ken’ichi Aoki Toshiyuki Sakaki Atsushi Kittaka

We synthesized two vitamin D3 analogues, 3 and 4, which have a shortened or elongated fluoro-side-chain based on 24,24-difluoro-25-hydroxyvitamin D3 (5) using an efficient convergent approach and studied their preliminary biological activity. Both analogues exhibited greater resistance to CYP24A1-mediated metabolism than the natural 25-hydroxyvitamin D3 (6), although their stability was lower than that of 5. Analogue 3 showed an approximately 100-fold lower human vitamin D receptor (hVDR)-binding affinity compared with 5 and 6. Despite this marked reduction in VDR-binding affinity, it demonstrated an approximately 1.5-fold increase in VDR-ligand binding domain (LBD) transcriptional activation of the natural ligand 6. In contrast, analogue 4 displayed moderate VDR-binding affinity and VDR-LBD transactivation compared with 5 and 6. We found that compound 3 is a unique vitamin D analogue with a fluorinated and shortened side-chain, exhibiting low binding affinity for hVDR but potent transcriptional activity through VDR-LBD with its long half-life; thus, 3 may serve as a basic structural skeleton for advancing medicinal chemistry and drug discovery.

Organics doi: 10.3390/org7020017

Authors: Alessandro Santarsiere Marianna Volgare Lucia Chiummiento

This work presents a revised total synthesis of two pharmacologically relevant benzofurans using newly developed environmentally friendly methodologies. In particular, we focused on establishing improved synthetic routes to stilbene dimers under milder and more sustainable reaction conditions. During our investigations, we optimized an efficient Sonogashira coupling carried out in water, which, followed by a Suzuki-like reaction conducted in dimethyl carbonate (DMC) in the absence of any transition metals, served as the key step for the synthesis of the benzofuran core.

Organics doi: 10.3390/org7020016

Authors: Jeltzlin Semerel Nigel John Pedro Fardim Wim Dehaen

Aloe-emodin is an anthraquinone with a wide range of medicinal applications, including anti-angiogenic, anticancer, antimicrobial, antiviral, anti-inflammatory, and antioxidant activities. In this review, the functionalization of aloe-emodin using various synthetic methods, including alkylation, condensation, esterification, the Finkelstein reaction, and the Kabachnik–Fields reaction was reported. The biological activity of the synthesized aloe-emodin derivatives is discussed, with a focus on their potential future applications as anticancer agents, enzyme inhibitors, anti-inflammatory agents, and antimicrobial agents. This review also discusses the structure–activity relationship (SAR) and the mechanism of action (e.g., molecular docking studies, cell membrane-disrupting capacity, and apoptosis studies). This review highlights the many contributions made towards the design and development of novel, biologically active aloe-emodin derivatives.

Organics doi: 10.3390/org7020015

Authors: Tiba M. Hameed Rafid M. Hashim S. J. Abed Raneen Hashim Ridha O. Al-Mohammed Baqer

A new series of eight novel etodolac-based 1,3,4-oxadiazoles was synthesized, characterized, and tested in silico in multidimensional routes, starting with etodolac, a well-known nonsteroidal anti-inflammatory medication (NSAID). In silico studies were performed prior to synthesis using the molecular docking technique in CCDC GOLD suite software (2025.3) to assess the interactions with two key targets involved in cancer pathogenesis: the crystal structure of the epidermal growth factor receptor EGFR tyrosine kinase domain (PDB ID: 4HJO) and the matrix metalloproteinase (MMP-9) complex (PDB ID: 5CUH). ADME studies were performed to assess the physicochemical properties of the synthesized molecules. Importantly, biotransformation prediction also indicated that the derivatives possess high metabolic stability, with hydroxylation of the thio-ether group as the primary predicted biotransformation route. All compounds were characterized using melting point, FT-IR, 1H-NMR, and 13C-NMR spectroscopy. In vitro and/or in vivo experiments are needed to confirm this preliminary anticancer study.

Organics doi: 10.3390/org7010014

Authors: Fabiola Hernández-García Emanuel Pérez-Martínez Raúl Colorado-Peralta Jesús Antonio Cruz-Navarro David Morales-Morales

Salophen-type Schiff base ligands derived from salicylaldehyde and naphthalene aldehydes were synthesized and coordinated to Ni(II) to obtain three nickel complexes (NiL1–NiL3), which were evaluated as heterogeneous electrocatalysts for the methanol electro-oxidation reaction (MOR) in alkaline media. The ligands and complexes were fully characterized by FT-IR, 1H NMR, EPR, DART-MS, and elemental analysis, confirming tetradentate coordination through imine nitrogen and phenoxide oxygen donors. Electrochemical studies were carried out using carbon paste electrodes modified with 15 wt % of each complex. Cyclic voltammetry revealed that the electrocatalytic activity is mediated by the Ni(II)/Ni(III) redox couple, with Ni(III) oxohydroxide species acting as the active sites for methanol oxidation. Among the evaluated systems, NiL1@CPE showed superior performance at low methanol concentrations, while NiL2@CPE and NiL3@CPE exhibited higher current densities at elevated methanol concentrations. Scan-rate studies indicated that the oxidation process is diffusion-controlled, and a linear response to methanol concentration was observed over a wide concentration range. The results demonstrate that ligand structure and coordination geometry play a crucial role in modulating the electrocatalytic behavior of Ni(II) Schiff base complexes, highlighting their potential as cost-effective molecular catalysts for alkaline methanol oxidation.

Organics doi: 10.3390/org7010013

Authors: Lucia Emanuele Rocco Racioppi Maurizio D’Auria

The study aimed to verify the possible use of DFT calculation in the prediction of the orientation in electrophilic aromatic substitution. An activated ortho/para orienting substrate, and a deactivated meta orienting substrate, were used in DFT calculations using B3LYP, B3PW91, BPV86, CAM-B3LP, HCTH, HSEH1PBE, LSDA, MPW1PW91, PBEPBE, TPSSTPSS, and WB97XD functionals. The results showed that the reactivity of anisole can be adequately described considering charge control in reaction performed in hard conditions (nitration), while frontier orbital control can play a role in reactions performed in softer conditions (chlorination). Nitration of benzaldehyde can be rationalized through Hirshfeld charges analysis. Neither the frontier orbital nor Mulliken charges approach adequately account for behavior observed in chlorination of benzaldehyde. The effect of different basis sets was tested performing calculations with B3LYP functional and aug-cc-pVDZ, 6-311G+(d,p), aug-cc-pVQZ, DGTZVP, and LanL2DZ basis sets. For anisole, all basis sets provided a HOMO electron density distribution consistent with experimental reactivity; Hirshfeld charges analysis consistently reproduced the observed reactivity of anisole across all tested basis sets. All the basis sets were able to explain the observed reactivity of benzaldehyde in hard experimental condition, while they failed to give a correct description when a softer reagent was used.

Organics doi: 10.3390/org7010012

Authors: Augusto Rivera Álvaro Castillo Jaime Ríos-Motta Diego Quiroga

In the present work, we describe the synthesis of a new heterocyclic derivative, 2-(naphthalen-1-yl)-2,3,5,6-tetrahydro-1H-isoquinolino[8,1,2-hij]quinazoline 1, using the reaction between the aminal 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane 2 (TATD) and 1-naphthylamine 3 as the first scaffold of a four-step linear synthetic route. In the first step, a condensation catalyzed by acetic acid in 96% ethanol was carried out, leading to the formation of the intermediate 3-(naphthalen-1-yl)-1,2,3,4-tetrahydrobenzo[h]quinazoline 4. Subsequently, this intermediate was acylated with 2-chloroacetyl chloride in the presence of triethylamine and under an inert atmosphere, obtaining the compound 2-chloro-1-(3-(naphthalen-1-yl)-3,4-dihydrobenzo[h]quinazolin-1(2H)-yl)ethan-1-one 5. In the third step, an intramolecular Friedel–Crafts cyclization was carried out using aluminum trichloride as a catalyst, yielding 2-(naphthalen-1-yl)-1,2,3,6-tetrahydro-5H-isoquinolino[8,1,2-hij]quinazolin-5-one 6. Finally, the reduction of this lactam with phosphorus pentachloride and sodium borohydride under anhydrous conditions led to the further closure of the polycyclic system, yielding the final product 1. The proposed route demonstrates the feasibility of using TATD 2 as a versatile precursor for constructing condensed heterocyclic systems of structural interest and potential relevance in advanced organic synthesis.

Organics doi: 10.3390/org7010011

Authors: Alexander V. Aksenov Nicolai A. Aksenov Nikolai A. Arutiunov Dmitrii A. Aksenov Anna M. Zatsepilina Daria I. Murashkina Maksim O. Shcheglov Sergei N. Ovcharov

2-Aryl-2-(3-indolyl)acetohydroxamic acids have emerged as promising antitumor agents; however, their poor pharmacokinetic profile remains a significant drawback. To address this limitation, we have synthesized a homolog of such acids—specifically 2-aryl-2-(3-indolyl)propionic acid (IC50 > 100 mM (U87)), along with several other derivatives: ethyl ester (IC50 > 100 mM (U87)), hydroxamate (IC50 21.2 ± 1.0 mM (U87)) and hydrazide (IC50 > 100 mM (U87)). The cytotoxicity of these compounds against glioblastoma cell lines was evaluated and compared to that of the parent acetohydroxamic acid derivatives.

Organics doi: 10.3390/org7010010

Authors: Yoonha Hwang Yeo Jin An Soohyun Sim Minjeong Shin

Understanding Li+ solvation structure is critical for the rational design of high- and localized high-concentration electrolytes. Here, we present a systematic investigation of tetrahydrofuran (THF)-based electrolytes with lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) using Raman spectroscopy and 7Li nuclear magnetic resonance to investigate the local solvation structures. By varying the THF:LiTFSI molar ratio, we observed a transition of Li+ solvation from solvent-separated ion pairs to contact ion pairs and aggregates, accompanied by increased structural heterogeneity and constrained local dynamics. Raman spectroscopy captures the evolution of Li+–anion coordination with increasing salt concentration, while 7Li NMR chemical shifts, line widths, and relaxation times provide complementary insight into changes in the electronic environment and symmetry of Li+ coordination. Electrolyte structure is further examined by introducing a hydrofluoroether co-solvent into a concentrated (THF)2–LiTFSI electrolyte. Raman results show that the local Li+–TFSI− coordination structure is preserved upon 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) addition, whereas NMR reveals subtle modifications of the ion-rich solvation clusters. These results provide fundamental insight into Li+ solvation and electrolyte localization, offering general design principles for advanced electrolyte systems.

Organics doi: 10.3390/org7010009

Authors: Hirokazu Okamoto Ayane Nomoto Dahiru Umar Liman Akib Bin Rahman Toshifumi Tojo Shin Aoki

Protein phosphorylation and dephosphorylation reactions of intracellular molecules catalyzed by enzymes such as kinases and phosphatases are essential reactions in a lot of cellular functions such as intracellular signal transduction in living systems. The design and synthesis of artificial enzyme mimics are important research topics in bioorganic and bioinorganic chemistry. In this paper, we report on the construction of artificial phosphatases via the supramolecular self-assembly of compounds such as an amphiphilic bis(Zn2+-cyclen) (cyclen = 1,4,7,10-tetraazacyclododecane) complex, barbital derivatives modified with benzocrown ethers and boronophenyl groups, and a copper(II) ion in a two-phase solvent system. We have developed a hypothesis whereby a mono(4-nitrophenyl)phosphate (MNP) substrate coordinates to the Cu2(µ-OH)2 core in supramolecular complexes and is activated either by Lewis acidic units such as alkali metal (Li+, Na+ and K+)-benzocrown ether complexes or by boronophenyl moieties. The findings suggest that supramolecular phosphatase functionalized with a benzo-12-crown-4-Li+ complex shows a higher level of activity in the MNP hydrolysis of a two-phase solvent system compared with that of our previous supramolecular phosphatases in terms of hydrolysis activity and catalytic turnover.

Organics doi: 10.3390/org7010008

Authors: Krzysztof K. Zborowski Urszula Lelek-Borkowska

This study aims to investigate the relative stability of the diaminodinitroethylene isomers (cis, trans, and gem). To achieve this goal, calculations at several levels of theory were carried out. The B3LYP, PBE0, and CAM-B3LYP functionals, based on density functional theory (DFT), were used. G4 and MP2 calculations were also executed. All calculation methods predicted that the gem isomer is the most stable, while the cis isomer is the least stable. The energy order obtained for the isomers studied was rationalized by analysis of the detected intramolecular hydrogen bonding, electron delocalization, charge distribution, and changes in atomic energies in the structures studied. The origins of the superior stability of the gem isomer are demonstrated and justified.

Organics doi: 10.3390/org7010007

Authors: Maria E. Filkina Lev A. Lintsov Victor A. Tafeenko Maxim E. Kukushkin Elena K. Beloglazkina

1,3-Dipolar cycloaddition reactions of nitrile imines are a powerful tool for the construction of spirocyclic frameworks, yet controlling chemoselectivity remains challenging when dipolarophiles contain multiple reactive sites. In this study, we investigated the cycloaddition of nitrile imines with 5-arylmethylene-2-methylthiohydantoins, which possess both exocyclic C=C and endocyclic C=N bonds. Nitrile imines were generated from hydrazonoyl chlorides under basic conditions and reacted with the thiohydantoin substrates under optimized reaction conditions. The cycloaddition proceeded smoothly, affording spiro-fused thiohydantoin–pyrazoline derivatives. In all cases, the reaction occurred selectively at the exocyclic C=C bond, while the C=N bond remained unreactive even in the presence of excess dipole. This chemoselectivity is attributed to the greater steric accessibility of the exocyclic double bond. These results clarify key factors governing nitrile imine chemoselectivity and provide a reliable approach to structurally complex spirocyclic thiohydantoin derivatives.

Organics doi: 10.3390/org7010006

Authors: Felipe Pinto Isadora Barbosa Frederico Conceição F. A. Olguin Gabrielle Peiter Julia C. M. Willig Helio A. Stefani Giancarlo V. Botteselle Flavia Manarin

A sustainable hybrid material, CuO/Cu2O, was synthesized using an aqueous extract of Curcuma longa L. as a reducing and stabilizing agent. The material was characterized by UV-Vis spectroscopy, FTIR, XRD, SEM, EDX, and TEM. XRD analysis revealed peaks corresponding to CuO and Cu2O phases with crystallite sizes of 15.88 nm and 16.71 nm, respectively. TEM images showed nearly spherical particles with some agglomeration and an average particle diameter of 8.17 nm. The hybrid material exhibited catalytic activity toward the synthesis of 1,2,3-triazoles in water, under low catalyst loading and mild reaction conditions. This work highlights the potential of Curcuma longa-mediated synthesis as a low-cost, eco-friendly alternative for producing efficient catalysts, contributing to the advancement of green chemistry and sustainable nanomaterial applications in organic synthesis.

Organics doi: 10.3390/org7010005

Authors: Wenqiao Zhou Chunming Liu

Commercially available resorufin was shown to function as an organic photocatalyst for visible-light-induced aqueous radical polymerization under low-irradiance illumination. Polymers with narrow molecular weight distributions and high monomer conversions were successfully synthesized from acrylate and acrylamide monomers. The photopolymerization catalyzed by resorufin was consistent with a reductive quenching mechanism. Good temporal control of the reaction was achieved by toggling visible light irradiation.

Organics doi: 10.3390/org7010004

Authors: Lin Lei Linjian Wu Yongjian Qiu Yaju Chen

The development of a metalloenzyme-like catalytic system for the efficient oxidation of olefins under a dioxygen (O2) atmosphere at room temperature is of significant interest in the field of catalysis. Herein, we present a highly active and selective aerobic epoxidation of olefins using metalloenzyme-like catalysts based on a non-heme ligand, tris(2-pyridylmethyl)amine (TPA). Notably, manganese chloride complexed with TPA (Mn(TPA)Cl2) demonstrated excellent activity for the epoxidation of trans-stilbene using O2 as the oxidant in the presence of a co-reductant at 30 °C. A quantitative conversion of 99% and high yield of 98%, as determined by gas chromatography using an external standard method, were achieved under optimum reaction conditions. Furthermore, Mn(TPA)Cl2 exhibited a good substrate tolerance to styrene derivatives with electron-withdrawing or electron-donating groups, cyclic olefins with different substituents and substitution degrees, as well as long-chain olefins. Coupled with a high turnover frequency (TOF) of up to 30,720 h−1, these results underscore the potential of Mn(TPA)Cl2 as a promising metalloenzyme-like catalytic platform for the aerobic synthesis of diverse epoxides from olefins under ambient conditions.

Organics doi: 10.3390/org7010003

Authors: Chinyere Chidimma Enyi Gloria Ihuoma Ndukwe Godswill Kuta Fekarurhobo Michael Oelgemöller

In this study, the singlet oxygen photosensitization potential of three natural African plant extracts was investigated using the photooxygenation of α-terpinene (1). Utilizing visible light, the Carpolobia lutea extract achieved high conversions towards the anthelmintic ascaridole (2) of >60% after 90 min of irradiation, while the extracts of Hibiscus sabdariffa and Justicia secunda failed to induce significant photoreactivity. Quenching using 1,4-diazabicyclo[2.2.2]octane (DABCO) confirmed a singlet oxygen pathway for irradiation with the C. lutea extract. Further separation of the C. lutea extract and subsequent photooxygenation screening established several active fractions for ascaridole generation. Advanced HPLC–MS analyses of these active fractions revealed several photosensitizing constituents. These findings establish C. lutea extract as a sustainable and effective photosensitiser with comparable performance to commercial dyes.

Organics doi: 10.3390/org7010002

Authors: Wei Wu Takahiro Kojima Hiroshi Sakaguchi

A conjugated helical cage, comprising two 1,3,5-tris(phenylethynyl)benzene units connected by diyne linkers, was successfully synthesized. X-ray crystallography revealed helical molecular structures with large twisted angles and a 1:1 mixture of P- and M-enantiomers. Variable-temperature-NMR measurement indicated the racemization process between the enantiomers occurs rapidly on the NMR timescale. The rapid interconversion is attributed to the flexible diyne linkages, even though they were believed to be rigid.

Organics doi: 10.3390/org7010001

Authors: Sung-Jen Hung Lo-Yun Chiang Yi-An Hong Kai-Chih Chang Yang-Je Cheng Hsin-Ying Wu Hussana Hamid Anren Hu Tzenge-Lien Shih Hao-Ping Chen

Our previous study demonstrated that thiophene-substituted synthetic curcumin analogs possessed better antibacterial activity and stability than natural curcumin, demethoxycurcumin, or bisdemethoxycurcumin in antibacterial photodynamic therapy (aPDT). In addition, the activity of the furan-substituted analogs was weaker than that of the thiophene-substituted compounds. As oxygen, sulfur, and selenium belong to the same group in the periodic table, the antibacterial and anticancer activities of these three different elemental analogs were compared and investigated. The thiophene-substituted analog (compound 3) exhibited the most potent antibacterial activity in aPDT experiments. However, the furan-substituted analog (compound 1) exhibited the most potent anticancer activity. These results indicate that the differences in atomic radii or energy levels in these compounds produce different cell-attack results on generated free radicals. Ruthenium(II) complexes have a good reputation for use in PDT for cancer treatment. Our results show that complexation of ruthenium(II) with thiophene-substituted curcumin analogs does not enhance their antibacterial or anticancer activity.

Organics doi: 10.3390/org6040054

Authors: Jovana S. Dragojević Žiko Milanović Kristina Milisavljević Nevena Petrović Jelena Petronijević Nenad Joksimović Vera M. Divac Marijana Kosanić Marina D. Kostić

A novel series of Schiff bases (3a–3k), incorporating tranexamic acid (TXA) and phenol-derived aldehydes via imine linkers, was synthesized and structurally characterized. The antimicrobial activity of the compounds was evaluated against a range of clinically and environmentally relevant bacterial and fungal strains. Among them, derivatives 3i and 3k, bearing bromine and chlorine substituents on the phenol ring, exhibited the most potent antimicrobial effects, particularly against Penicillium italicum and Proteus mirabilis (MIC as low as 0.014 mg/mL). To elucidate the underlying mechanism of action, in silico molecular docking studies were conducted, revealing strong binding affinities of 3i and 3k toward fungal sterol 14α-demethylase (CYP51B), with predicted binding energies surpassing those of the reference antifungal ketoconazole. Additionally, UV-Vis and fluorescence spectroscopy assays demonstrated good stability of compound 3k in PBS and its effective binding to human serum albumin (HSA), respectively. ADMET and ProTox-II predictions further supported the drug-likeness, low toxicity (Class 4), and favorable pharmacokinetic profile of compound 3k. Collectively, these findings highlight TXA–phenol imine derivatives as promising scaffolds for the development of next-generation antimicrobial agents, particularly targeting resistant fungal pathogens.

Organics doi: 10.3390/org6040053

Authors: Giovanni Bella Giuseppe Bruno Antonio Santoro

Density functional theory (DFT) and its extension, time-dependent DFT (TD-DFT), have become fundamental tools for modeling chiral excited states and supporting experimental chiroptical spectroscopies. In this connection, the interest in understanding the asymmetric emission through the circularly polarized luminescence (CPL) technique peaked in the current decade. In the present work, we are computationally faced with an emerging class of luminophores which combines the luminogenic source of the BODIPY unit with the intrinsic chirality of the helicene pendant to obtain a chiral radiative deactivation. In particular, a meso-substituted BODIPY-[6]helicene was deeply examined through a DFT multistep approach to attain an appreciable level of theory for the CPL simulation. Among the multitude of alternatives, TPSSTPSS exchange-correlation functional with 6-311G(d,p) basis set revealed to be the best computational protocol to emulate the CPL spectral profile with regard to peak intensity, band position, and chiral sign for both M and P form.

Organics doi: 10.3390/org6040052

Authors: Mina Dumre Pandey Tahir Awais Krishna Pandey Samsul Arafin Eli Jones Kyle N. Plunkett

The direct chlorination, bromination and azidation of beta keto esters, 2-acetyl-1-tetralone and methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate is achieved utilizing anion-coordinated hypervalent iodine benziodazoles derived from hypervalent iodine macrocycles. This reaction, which introduces the halogen, azido or cyano group at the alpha carbon atom of beta keto esters, is accomplished in chloroform at 60 °C and results in the formation of a chiral center. Depending on the structure of the benziodazole reagent, the reaction can have mild enantioselectivity. The reaction between 2-acetyl-1-tetralone and phenylalanine-derived hypervalent iodine benziodazoles results in the chlorinated product with 26% enantiomeric excess.

Organics doi: 10.3390/org6040051

Authors: Polidoros Chrisovalantis. Ioannou Nikolaos Tsoureas Sevasti-Panagiota Kotsaki

The synthesis of a small library of fused Cyclic Aryl Amino Carbon (f-CArAC) carbene precursors in the form of 1,1,2,4-tetraaryl-1H-isoindol-2-ium triflate (6), (7-R) (R = tBu, CF3) or 3,3-dimethyl-2,8-bis-arene-substituted-3,4-dihydro-isoquinolin-2-ium hydrogen-dichloride (8) and 2,4,8-tri(substituted)-isoquinolin-2-ium tosylate salts (12) has been achieved. All of them feature an arene incorporated on the annulated benzene ring of the corresponding heterocycle, introduced at the early stages of their synthesis via the Suzuki cross-coupling reaction between 2,6-dibromo-benzaldehyde and the desired aryl boronic acid. The terphenyl-2′carbaldehyde by-products of this Suzuki reaction are useful starting points for the preparation of two new iminium iodide salts (10-R) (R = H, CF3) as potential precursors to access ACyclic Amino Carbon (ACAC) carbenes. Compounds (6) and (7-tBu) react readily with hydroxide either in THF or in a biphasic Et2O/aqueous OH− solution to produce the substituted isoindolinols (13) and (14), respectively. The thermal dehydration of the former generates the corresponding f-CArAC carbene in situ, which is trapped by Cu(I)Cl furnishing, a rare example of a two-coordinate Cu(I) complex (15) supported by this new ligand scaffold.

Organics doi: 10.3390/org6040050

Authors: Gaëtan Ossard Milene Macedo Hornink Sabrina Lebrequier David-Alexandre Buisson Jean-Christophe Cintrat Eugénie Romero

High-Throughput Experimentation has undergone an outstanding evolution in the past two decades and has proven to be a game-changer in the acceleration of reaction discovery and optimization. Despite a good implementation in the pharmaceutical industry and a demonstrated accessibility to the technology, the generalization of High-Throughput Experimentation as a standard method for optimizing reactions is not yet observed. The perspective aims at discussing the necessity of generalizing such technologies, supported by the case study: the optimization by High-Throughput Experimentation of a key step in the synthesis of Flortaucipir, an FDA-approved imaging agent for Alzheimer’s diagnosis.

Organics doi: 10.3390/org6040049

Authors: Shaima Hkiri Neslihan Şahin Romain Sabourin Rémi Brandt İsmail Özdemir David Sémeril

A series of five cobalt(II) complexes, dichloro-bis(1-benzyl-benzimidazole)-cobalt(II) (1a), dichloro-bis[1-(4-fluorobenzyl)-benzimidazole]-cobalt(II) (1b), dichloro-bis((Z)-1-styryl-benzimidazole)-cobalt(II) (1c), dichloro-bis[(Z)-1-(2-fluorostyryl)-benzimidazole]-cobalt(II) (1d) and dichloro-bis(1-cinnamyl-benzimidazole)-cobalt(II) (1e), were evaluated in ethylene dimerization. Four of these complexes were described for the first time and fully characterized by IR, elemental analysis, mass and NMR spectroscopy. In the solid state, the cobalt atom exhibited a typical tetrahedral geometry and was found to be coordinated to two chlorine atoms and two benzimidazole rings. In the presence of 20 bar of ethylene and diethylaluminium chloride as a co-catalyst, the complex with styryl substituents on the benzimidazole rings, complex 1c, exhibited the highest activity with a turnover frequency of 3430 mol(ethylene)·mol(Co)−1·h−1.

Organics doi: 10.3390/org6040048

Authors: Liling Pan Ke Yang

4H-Benzo[d][1,3]oxathiin-4-ones and 4H-benzo[d][1,3]dioxin-4-ones, as important classes of sulfur- or oxygen-containing heterocyclic compounds, possess significant application potential in the fields of pharmaceutical chemistry, agriculture, and the food industry due to their distinctive structural characteristics and diverse biological activities. In recent years, efficient synthetic strategies for these compounds have witnessed remarkable progress. This review summarizes significant advancements in the construction of these heterocycles from 2012 to the present.

Organics doi: 10.3390/org6040047

Authors: Cilong Chen Jinrui Liu Bangsen Li Dashuai Zhang Peisong Zhang Jianjun Shi Zaifeng Shi

Rubber material with high elasticity and viscoelasticity has become the most widely used universal material, and the study of the aging failure mechanism of rubber has been meaningful research in the polymer materials field. Cis-polyisoprene was employed to analyze the mechanism of oxidative degradation under artificial UV irradiation, and the GQDs/g-C3N4 photocatalysis with a 2D layered structure prepared by the method of microwave-assisted polymerization enabled to accelerate the degradation procedure. The results showed that the oxidation of cis-polyisoprene occurred during the irradiation for 3 days and the structure of cis-polyisoprene changed. The α-H of the double bond was attacked by oxygen to form hydroperoxide. Then, aldehydes and ketones generated as the addition reaction of double bonds occurred. The content of the hydrogen of C=C reduced, and the oxidative degradation was dominant at the initial aging stage. The crosslinking reaction was dominant at the final aging stage and the average molecular weight decreased from 15.49 × 104 to 8.78 × 104. The GQDs could promote the charge transfer and the photodegradation efficiency and inhibit the electron–hole recombination. The light capture ability of GQDs was improved after compositing with g-C3N4. The free radicals ·O22− generated after adding GQDs/g-C3N4 nanoparticles, and the molecular weight of cis-polyisoprene decreased to 5.79 × 104, with the photocatalytic efficiency increasing by 20%. This work provided academic bases and reference values for the application of photocatalysts in the field of natural rubber degradation and rubber wastewater treatment.

Organics doi: 10.3390/org6040046

Authors: Aigul E. Malmakova Alan M. Jones

This review offers a focused overview of the strategies used to build and modify phenothiazine (PTZ) derivatives. It covers both classical synthetic approaches and advances reported since 2014, including transition metal-catalyzed transformations and greener techniques, such as electrosynthesis, microwave-assisted reactions, and ultrasound-promoted methods. Each strategy is evaluated with respect to efficiency, scalability, and sustainability. In parallel, the review surveys the diverse bioactivity profiles of PTZ derivatives, ranging from antipsychotic, anticancer, and antimicrobial activities to emerging applications in photodynamic therapy and neuroprotection. By correlating synthetic accessibility with biological potential, this review provides an integrated perspective that highlights advances achieved since 2014 and outlines future opportunities for rational PTZ design and applications.

Organics doi: 10.3390/org6040045

Authors: Savina Stoyanova Milen G. Bogdanov

This study examined twenty-eight N-methylimidazolium ionic liquids (ILs) with various substituents and anions to assess their impact on the activity of Carnitine Acetyltransferase (CAT), an indispensable enzyme in human metabolism. In vitro experiments demonstrated that these compounds inhibited CAT in a concentration-dependent manner, with IC50 values ranging from 0.93 to 30.8 mM. Structural analysis of the ILs revealed the following structure–activity relationships: (i) the length of the hydrocarbon chain at N3 markedly affects CAT activity, with longer chains resulting in stronger inhibition; (ii) the degree of unsaturation and the presence of polar groups are not essential for increased activity; (iii) the effect of the anion aligns with the Hofmeister series. One of the most potent compounds, 1-decyl-3-methylimidazolium bromide [C10C1im]Br, was identified as a mixed inhibitor of CAT with a Ki of 0.77 mM. These findings raise concerns about the biocompatibility of commonly used imidazolium ILs, as they may interfere with fatty acid oxidation by inhibiting their cellular transport.

Organics doi: 10.3390/org6040044

Authors: Diego Quiroga Jaime Ríos-Motta Augusto Rivera

4,4′-substituted-2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bisphenols (1a–d) and 2,6-bis{[3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substitutedphenols (2a–b) were synthesized via microwave (MW) irradiation of aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,70.11,16]icosane 2 with p-substituted phenols. Microwave (MW) irradiation improved reaction rates and yields at 80 °C. Compounds 1a–d were racemic, and 2a–b were diastereomeric. NMR spectra revealed key signals for the perhydrobenzimidazole fragment, aromatic rings, and aminal carbons. Differences in the 13C NMR spectra highlighted structural variations, such as distinct carbonyl and methoxyl signals in 2d. MW irradiation at higher temperatures (100–120 °C) reduced yields of 1, especially for phenols with methyl (Me) and methoxy (OMe) groups, suggesting a shift toward the formation of compound 2. Additionally, higher temperatures led to polymerization byproducts, emphasizing the impact of MW energy on reaction pathways. These results provide valuable insights for designing molecules with potential applications in materials science and medicinal chemistry.

Organics doi: 10.3390/org6030043

Authors: Péter Kisfaludi Sára Spátay Péter Huszthy Ádám Golcs

Although sulfonated acridines and acridones are valuable scaffolds in diagnostics and materials science, to our best knowledge, there is no comprehensive study that addresses how the degree of sulfonation depends on reaction parameters. To fill this gap, we investigated the sulfonation behavior of unsubstituted acridine and acridone under classical conditions, using sulfuric acid, oleum, and chlorosulfonic acid. A factorial experimental design was applied to systematically evaluate the influence of temperature and reagent excess on the extent of sulfonation, while keeping the reaction time constant. Products were analyzed by HPLC–MS/MS to determine the degree of sulfonation and its distribution. Regioselectivity and product isolation were not addressed in this study. Our results provide a foundational dataset for controlling sulfonation level for these heterocycles and can help future synthetic applications where defined sulfonation patterns are desired.

Organics doi: 10.3390/org6030042

Authors: Elisa Leyva Johana Aguilar Silvia E. Loredo-Carrillo Ismael Acosta-Rodríguez

Several fluoro phenyl triazoles were synthesized using click chemistry between fluoro phenyl azides and phenyl acetylene. Under ultrasound irradiation, this synthetic procedure was performed with Cu (I) in the presence of 1,10-phenanthroline. It is fast with high yields of target compounds. In addition, fluoro phenyl triazoles were evaluated against Candida albicans. The inhibition percentage of yeast growth was investigated using different concentrations of triazoles. Compounds containing a fluorine atom in 2, 4, 2,6, and 2,4,6 positions inhibited a higher percentage of yeast growth. All of the triazoles showed inhibition of the yeast–mycelium transition, which was related to pathogenicity of yeast strain C. albicans.

Organics doi: 10.3390/org6030041

Authors: Abdukhakim A. Ziyaev Sobirdjan A. Sasmakov Turdibek T. Toshmurodov Jaloliddin M. Abdurakhmanov Saidazim A. Ikramov Shukhrat Sh. Khasanov Oybek N. Ashirov Mavluda A. Ziyaeva Dilrabo B. Begimqulova

Derivatives of 1,2,4-triazole-3-thione exhibit a variety of biological activities, including antimicrobial (e.g., compounds 31d–k, 32d, 36f), antitumor (e.g., 71, 77a–c, 82g, 94h), anti-inflammatory, analgesic (100a, 102, 105), antidiabetic, and antioxidant (104, 138) activity. These compounds can be efficiently synthesized by classical methods (e.g., cyclization of thiosemicarbazides) and/or modern “green” approaches, which allow for obtaining target compounds in high yields (up to 96%). The presence of electron-donating groups (e.g., -OH, -OCH3) enhances antimicrobial and antitumor activity. Substituents in the aromatic ring (e.g., NO2, Cl) affect the ability to bind to biological targets such as DNA or enzymes. 1,2,4-triazole-3-thiones can also be used as fungicides and herbicides (e.g., 131), demonstrating high efficiency against phytopathogens. Thus, 1,2,4-triazole-3-thione derivatives are multifunctional compounds with high potential for the development of new drugs and agrochemicals. Their further study and modification can lead to the creation of more effective and safer drugs.

Organics doi: 10.3390/org6030040

Authors: Wender Alves Silva Sayuri Cristina Santos Takada Felipe Marques Nogueira Luiz Arthur Ramos Almeida

Catalytic transfer hydrogenation (CTH) and microwave-assisted organic synthesis (MAOS) have each advanced the sustainability of reduction chemistry; however, their combined application to conjugated enones remains largely unexplored. To the best of our knowledge, no unified protocol has been reported for the rapid, one-pot conversion of chalcones into saturated alcohols under microwave irradiation. Herein, we report a concise and green method that integrates MAOS with Pd/C-catalyzed CTH, employing inexpensive ammonium formate in ethanol. In contrast to state-of-the-art hydrogenations that require pressurized H2 or costly metal complexes, our strategy (i) achieves complete conversion within 20 min at 60 °C, (ii) tolerates both electron-rich and electron-poor substrates, (iii) reduces nitro-substituted chalcones in a single step, and (iv) consumes < 0.005 kWh per reaction—an approximately 250-fold energy saving relative to conventional procedures. These results position microwave-driven CTH as a scalable alternative for synthesizing pharmacologically relevant saturated alcohol scaffolds from readily available chalcones.

Organics doi: 10.3390/org6030039

Authors: Jeremy A. Rodríguez-Vargas Sebastián H. Díaz-Rodríguez Víctor G. Vergara-Rodríguez Ángel Vidal-Rosado Cristtian Rivera-Torres Alejandra Ríos-Rodríguez Martín Rodríguez-Del Valle Daliana Agosto-Disdier Marielys Torres-Díaz Kai H. Griebenow Raúl R. Rodríguez-Berríos

The search for bioactive compounds with antioxidant properties is critical in combating oxidative stress-related diseases and advancing novel therapeutic agents. Azo dyes, traditionally used in textiles, food, and cosmetics, have recently attracted attention due to their emerging biological activities, including antioxidant potential. In this study, we synthesized and characterized 267 azo dyes derived from natural phenolic cores such as salicylic acid, syringol, and 5,6,7,8-tetrahydro-2-naphthol. Eighteen of these compounds are novel. Structural characterization was performed using NMR, UV-Vis, IR spectroscopy, and mass spectrometry. Antioxidant activity was assessed using in vitro assays with ABTS radical scavenging method. SAR analysis revealed that dyes derived from syringol and 5, 6, 7, 8-tetrahydro-2-naphthol showed the most consistent and potent antioxidant activity. Notably, azo dyes bearing fluoro and nitro substituents in the para position exhibited the lowest IC50 values, highlighting the influence of electron-withdrawing groups and substitution patterns on antioxidant behavior. This work establishes a precedent for SAR-driven evaluation of azo dyes using ABTS and supports their further exploration as functional antioxidant agents in medicinal chemistry.

Organics doi: 10.3390/org6030038

Authors: María Isabel Amil-Miranda Armando Pineda-Contreras Francisco Javier Martínez-Martínez Marcos Flores-Álamo Hector García-Ortega Juan Saulo González-González

Phenytoin is an anticonvulsant drug that suffers from low aqueous solubility. The formation of phenytoin salts is a strategy employed to address this issue. A phenytoin–piperidine salt (PPD–PNT) was synthesized by solvent-assisted grinding and characterized by infrared (IR) spectroscopy, 1H and 13C Nuclear Magnetic Resonance (NMR), and powder and single crystal X-ray diffraction. The IR and NMR spectra obtained differed from those of the starting compounds, showing shifts in the N-H and C=O group signals, as well as the appearance of NH+ signals, indicating proton transfer and salt formation. Powder X-ray diffraction confirmed the formation of a new solid phase corresponding to the salt. Single crystal X-ray diffraction showed the molecular structure of the PPD–PNT salt.

Organics doi: 10.3390/org6030037

Authors: Luis A. Méndez-Delgado Mónica Martínez-Montiel Alma Fuentes-Aguilar Socorro Meza-Reyes Sara Montiel-Smith José Luis Vega-Baez José M. Padrón Penélope Merino-Montiel

A total of 24 novel steroidal derivatives were synthesized, including 1,3,4-thia(selena)diazolines and structurally unique spirothiadiazolines, obtained through intramolecular cyclization under standard acetylation conditions. This strategy was further extended to the construction of a novel dimeric compound bearing a thiadiazoline linker. Seleno- and thiosemicarbazone precursors were derived from various functionalized steroidal monomers and dimers via straightforward synthetic protocols. Key intermediates included aldehyde 7 and ketones 16, 19, and 24. Rotameric equilibria were observed in certain thiosemicarbazones, attributed to partial double-bond character in the N–CS bond. Cyclization yielded heterocyclic systems as epimeric mixtures, and in some cases, inseparable mixtures of isomers were obtained due to low diastereoselectivity. Full structural elucidation of epimeric pairs was achieved using 2D NMR and IR spectroscopy, with compounds 2, 3, 5, 11, 17, 27, 28a, and 28b further confirmed by single-crystal X-ray diffraction. Preliminary antiproliferative assays against human cancer cell lines revealed GI50 values below 10 µM for compounds 21, 22, and 27.

Organics doi: 10.3390/org6030036

Authors: Liping Wang Mingyu Zhang

Porous carbon-loaded MnO was prepared via a combination of the sol–gel method and the chemical blow molding method using polyvinylpyrrolidone (PVP) and manganese nitrate as starting materials. SEM, EDX, TEM, FTIR, XRD, XPS, nitrogen adsorption–desorption, and elemental analysis were used to assess its physical and chemical characteristics. Furthermore, the adsorption property of porous carbon-loaded MnO for hexavalent chromium (Cr(VI)) in polluted water was investigated in detail. The results demonstrated that large numbers of MnO nanoparticles were evenly mounted on the surfaces of carbon walls, with a uniform distribution of C, N, and O elements. The BET surface area was 46.728 m2/g, and the pore sizes of porous carbon ranged from 2 nm to 10 nm. Additionally, abundant surface functional groups were found in porous carbon-loaded MnO, a result consistent with XPS data and applicable to the adsorption of heavy metals from aqueous solutions containing Cr(VI). The Freundlich model fitted the adsorption isotherm well, and the pseudo−second−order model precisely matched the adsorption kinetics. According to the study results, the adsorption was multilayer, and the adsorption process involved an endothermic reaction. These results indicate that this is a feasible way to synthesize a high−efficiency adsorbent for the removal of harmful heavy−metal ions from wastewater.

Organics doi: 10.3390/org6030035

Authors: Suzana Apostolov Dragana Mekić Marija Mitrović Slobodan Petrović Gyöngyi Vastag

Modern agriculture relies heavily on the use of pesticides, with one-third of them being herbicides. Chloroacetamides are the most widely used herbicides because of their high effectiveness, but their extensive use poses environmental challenges and threatens the health of living organisms due to toxicity risks. Since the pharmacokinetic behavior and toxicity of a compound are influenced by its lipophilicity, this essential physicochemical parameter for disubstituted chloroacetamides was determined in silico and experimentally through thin-layer chromatography on reversed phases (RPTLC C18/UV254s) in mixtures of water and distinct organic modifiers. The pharmacokinetic profile of chloroacetamides was analyzed by using the BOILED-Egg model. The correlation between the obtained chromatographic parameters and software-based lipophilicity, pharmacokinetic, and ecotoxicity predictors of the studied chloroacetamides was assessed by using linear regression, but more comprehensive insight was obtained through multivariate methods—Cluster Analysis and Principal Component Analysis. It was observed that the total number of carbon atoms in the structure of their molecules, along with the type of hydrocarbon substituents, are the most important factors affecting lipophilicity, pharmacokinetics, and potential toxicity to non-target organisms.

Organics doi: 10.3390/org6030034

Authors: Lucia Emanuele Maurizio D’Auria

DFT calculations at the B3LYP/aug-cc-pVDZ level of theory on some aromatic substrates showed that in the HOMO (Highest Occupied Molecular Orbital) of nitrobenzene, the atomic coefficients are not in agreement with the meta-directing behavior of this compound. The atomic coefficients are the same in the ortho and in the meta positions. The HOMO (or NHOMO (Next Occupied Molecular Orbital) in the case of benzaldehyde) is not in agreement with the experimental results when deactivating, meta-orienting compounds are considered. Mulliken charges sometimes are not able to explain the observed reactivity. Hirshfeld charges allow us to predict the orientation of the attack of an electrophile on the aromatic ring, with the exception of nitrobenzene. Both HOMO atomic coefficients and charges are in agreement with the experimental results when deactivating, ortho-para orienting, and activating compounds are tested.

Organics doi: 10.3390/org6030033

Authors: Mengran Chen Dongmei Xie Hongqing Zhou Pengan Zong

Polyaniline (PANI) based thermoelectric materials have attracted much attention in flexible energy harvesting devices due to their unique molecular structure, excellent chemical stability, and low cost. However, the intrinsic thermoelectric performance of intrinsic PANI makes it difficult to meet the needs of practical applications due to its low electronic transport properties. This review focuses on the preparation methods and key strategies for developing high-performance PANI-based thermoelectric materials. It aims to comprehensively update knowledge regarding synthesis methods, microstructures, thermoelectric properties, and underlying mechanisms. The overall goal is to provide timely insights to promote the development of high-performance PANI-based thermoelectric materials.

Organics doi: 10.3390/org6030032

Authors: Lei Li

Ultra-high-molecular-weight polyethylene (UHMWPE) is a pivotal material in engineering and biomedical applications due to its exceptional mechanical strength, wear resistance, and impact performance. However, its extreme melt viscosity, caused by extensive chain entanglements, severely limits processability via conventional melt-processing techniques. Recent advances in catalytic synthesis have enabled the production of disentangled UHMWPE (dis-UHMWPE), which exhibits enhanced processability while retaining superior mechanical properties. Notably, heterogeneous catalytic systems, utilizing supported fluorinated bis (phenoxy-imine) titanium (FI) catalysts, polyhedral oligomeric silsesquioxanes (POSS)-modified Z-N catalysts, and other novel catalysts, have emerged as promising solutions, combining structural control with industrial feasibility. Moreover, optimizing polymerization conditions further enhances chain disentanglement while maintaining ultra-high molecular weights. These systems utilize nanoscale supports and ligand engineering to spatially isolate active sites, tailor the chain propagation/crystallization kinetics, and suppress interchain entanglement during polymerization. Furthermore, characterization techniques such as melt rheology and differential scanning calorimetry (DSC) provide critical insights into chain entanglement, revealing distinct reorganization kinetics and bimodal melting behavior in dis-UHMWPE. This development of hybrid catalytic systems opens up new avenues for solid-state processing and industrial-scale production. This review highlights recent advances concerning interaction between catalyst design, polymerization control, and material performance, ultimately unlocking the full potential of UHMWPE for next-generation applications.

Organics doi: 10.3390/org6030031

Authors: Juan F. Ortuño Alessio Ghisolfi Raquel Almansa Olga Soares do Rego Barros Ana Sirvent José M. Sansano Francisco Foubelo

The synthesis of cannabigerol—a cannabinoid with significant pharmaceutical potential—is described. The synthesis involves four stages. In the first step, (E)-non-3-en-2-one reacts with dimethyl malonate to yield a cyclic enone, which is subsequently oxidized with bromine to produce the olivetol ester. This ester then undergoes an alumina-catalyzed coupling reaction with geraniol, followed by ester hydrolysis to obtain cannabigerol. By modifying the chain length of the enone in the initial step and employing allylic alcohols other than geraniol, a range of cannabigerol derivatives can be synthesized, including the natural product cannabigerovarin.

Organics doi: 10.3390/org6030030

Authors: Jingwei Wu Yongzhu Zhou Lei Zhang Jie Zhang Pei Song Xiaoling Wang Cuihong Wang

Density functional theory calculations were performed to elucidate the mechanistic details and origins of the selectivity of the nickel-catalyzed hydroboration of vinylarenes using B2pin2/MeOH. The catalytic cycles involved four sequential elementary steps: hydronickelation, anion exchange, transmetalation, and reductive elimination. Kinetic analyses identified hydronickelation as the rate-determining step with an activation barrier of 19.8 kcal/mol, while transmetalation proceeded through a stepwise mechanism characterized by two distinct transition states. Comprehensive analyses of the relevant transition structures and energetics demonstrated that the observed R-enantioselectivity (94% ee) originated from favorable nonbonding interactions. Lastly, our calculations suggested that the Markovnikov regioselectivity was predominantly governed by steric factors rather than electronic effects.

Organics doi: 10.3390/org6030029

Authors: Raúl R. Rodríguez-Berríos José A. Prieto

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products.

Organics doi: 10.3390/org6030028

Authors: Ricardo Cartes-Velásquez Felipe Morales-León Franco Valdebenito-Maturana Pablo Sáez-Riquelme Nicolás Rodríguez-Ortíz Hernán Carrillo-Bestagno

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential.

Organics doi: 10.3390/org6020027

Authors: Danielle Tapia Bueno Amanda Fonseca Leitzke Rayane Braga Martins Daisa Hakbart Bonemann Emanuel Gomes Bertizzolo Gabrielly Quartieri Sejanes Juliana Porciúncula da Silva Lucas Minghini Gonçalves Neftali Lenin Villarreal Carreno Claudio Martin Pereira de Pereira

Papilloscopy, the science of human identification through fingerprints, has seen notable advancements in developing less toxic latent fingerprint developers (LFDs), especially from natural feedstock. Tannins, the second most abundant natural polyphenol, present a potential eco-friendly and cost-effective alternative, with no record of their use as LFDs in the existing literature. This study characterized four types of tannins from black wattle, using Fourier Transform Infrared Spectroscopy, revealing key functional groups like C=O, C=C, and O–H. Ultraviolet–visible absorption spectra showed similar behaviors for all tannins, indicating phenolic and benzenoid structures. Energy-dispersive X-ray Spectroscopy identified high concentrations of chlorine, sodium, potassium, and sulfur, naturally found in biomass and soil. Finally, elements in significant concentrations, such as sodium, potassium, iron, zinc, and copper, were found through the incineration of the spent bark. On the basis of these findings, the tannin with the highest potential for LFD was selected. Combining this tannin with spent bark ash resulted in a composite whose performance was evaluated using different methods, including depletion studies, tests with various donors, and assessments on different surfaces. The results demonstrated that this combination significantly enhanced the material’s efficiency by integrating organic and inorganic properties, which improved visual contrast and powder adhesion.

Organics doi: 10.3390/org6020026

Authors: Zhikang Wang Mingjie Yang Weibo Yang Zhongzheng Gao Hui Zhao Gang Wei Jifu Sun

The interaction between cucurbit[8]uril (Q[8]) and the guest 1-methyl-4-(4-(1-methylpyridin-1-ium-4-yl)benzamido)pyridin-1-ium (PB2+) has been thoroughly investigated. Multiple techniques were employed, including 1H NMR spectroscopy, mass spectrometry, isothermal titration calorimetry (ITC), UV–vis absorption spectrophotometry, and quantum chemistry calculations. The experimental results and calculation analysis have clearly shown that in aqueous solution, the host Q[8] preferentially encapsulates the phenylpyridinium salt moiety of the PB2+ guest within its hydrophobic cavity, forming a 1:2 inclusion complex.

Organics doi: 10.3390/org6020025

Authors: Ying An Ying Sun Zhenming Yin

A macrocyclic receptor based on azopyrrole and polyether was synthesized, and its structure was characterized by NMR (1H and 13C), HRMS and X-ray crystallography. In the solid state, the macrocyclic molecules could bind methanol through a pair of N-H…O hydrogen bonds and further self-assembled into tubular structures through C-H…N hydrogen bonds. This revealed that the crystal could still keep its porous properties after the included molecules were removed. The UV–Vis titration indicates that the macrocylic receptor can chromogenically and selectively sense fluoride ion in DMSO solution, and the sensing mechanism was rationalized by 1H NMR.

Organics doi: 10.3390/org6020024

Authors: Artem P. Ermolenko Diana Y. Pobedinskaya Elena K. Avakyan Anastasia A. Borovleva Alexander N. Larin Ivan V. Borovlev Oleg P. Demidov

A series of previously poorly studied heterocyclic compounds, 10R-pyrido[4,3-a]phenazines, including the previously unknown parent compound, has been synthesized. The proposed synthetic approach is remarkable for its simplicity, due to the ease of the synthesis of the starting materials from readily available precursors, and is characterized by high yields of the target products, achievable under both acidic and basic catalysis. The paper discusses the synthesis conditions, optimization procedures, and X-ray crystallographic data.

Organics doi: 10.3390/org6020023

Authors: Isis Apolo Silveira de Borba Jamile Buligon Peripolli Angélica Rocha Joaquim Fernando Fumagalli

Heterocycle cores are widely used in medicinal chemistry for developing bioactive compounds. In this scenario, using cheap and accessible starting material to build these heterocycles is desirable to obtain new drug candidates for cost-efficient processes. One easily accessible source of starting material are amino acids. Usually, these compounds are employed in peptide synthesis, but their use for building heterocycle frameworks presents another appealing opportunity. Therefore, this review highlights the application of histidine and tryptophan, two heteroaromatic amino acids, in fused heterocyclic scaffold synthesis and their use in bioactive compounds.

Organics doi: 10.3390/org6020022

Authors: Tian Zhao Shilin Peng Jiangrong Yu Jiayao Chen Fuli Luo Pengcheng Xiao Saiqun Nie Yi Chen

Metal–organic frameworks (MOFs), particularly zirconium-based frameworks (Zr-MOFs), have gained significant attention in recent years due to their unique structural and functional properties. This review focuses on eco-friendly synthetic methods for producing Zr-MOFs, addressing the environmental impacts and costs associated with conventional synthesis, which often relies on hazardous reagents and harsh conditions. We explore various green synthesis strategies, including the selection of raw materials (such as using zirconium acetate), organic ligands (recycling waste materials for ligand synthesis), and synthesis methods (solvothermal, microwave-assisted, ultrasound-assisted, electrochemical, and mechanochemical approaches). Additionally, the application of Zr-MOFs in photocatalysis and electrocatalysis is examined, highlighting their potential for environmental purification and energy conversion. Despite the progress made in laboratory settings, challenges remain in achieving cost-effectiveness, material stability, and scalability for industrial applications. Future research should concentrate on enhancing synthesis efficiency, optimizing catalytic properties, investigating structure–property relationships, and expanding applications to novel catalytic reactions, thus ensuring Zr-MOFs can contribute to sustainable development in chemical science and technology.

Organics doi: 10.3390/org6020021

Authors: Maria C. Vagi Andreas S. Petsas Dionysia Dimitropoulou Melpomeni Leventelli Anastasia D. Nikolaou

This study concerns the investigation of the sorption and desorption phenomena of the organic dye methylene blue (MB) on three different marine sediments and non-living biomass of the seagrass species Posidonia oceanica. All tested adsorbents were of natural origin and were collected from unpolluted coasts of the North Aegean Sea (Greece). The batch equilibrium technique was applied and MB concentrations were determined by spectrophotochemical analysis (λ = 665 nm). The experimental results showed that all four isotherm models, Freundlich, Langmuir, Henry, and Temkin, could describe the process. The normalized to organic matter content adsorption coefficients (KOM) ranged between 33.0765 and 34.5279 for the studied sediments. The maximum adsorption capacity (qmax) of sediments was in the range of 0.98 mg g−1 and 6.80 mg g−1, indicating a positive correlation with the adsorbents’ organic matter content, textural analysis of fine fraction (<63 μm), and specific surface area. The bioadsorption of MB on P. oceanica biomass resulted in 13.25 mg g−1 up to 17.86 mg g−1 adsorption efficiency. Desorption studies revealed that the studied dye in most cases was very strongly adsorbed on studied matrices with extremely low quantities of seawater extractable amounts (≤1.62%). According to the experimental findings, phycoremediation by using P. oceanica can be characterized as an efficient method for the bioremediation of dye-polluted wastewater.

Organics doi: 10.3390/org6020020

Authors: Teresa Celestino

In the chemical education field, the Johnstone’s triangle represents three learning levels (symbolic, macroscopic, and molecular) needed for students. Afterwards, Mahaffy suggested a tetrahedron model based on this triangle, where the top represents the human element. Subsequently, Sjöström proposed a subdivision of the top into three other levels: applied chemistry, socio-cultural context, and critical–philosophic approach. These six dimensions of chemical knowledge will be examined in relation to the discovery of aniline, its chemistry and applications. The historical and epistemic aspects of this topic, gradually broadening the focus to the social, political, and artistic backdrop, can provide a more effective approach to teaching the subject. The major impact of the synthetic dye industry makes this field of study particularly important for a Bildung-focused chemistry education.

Organics doi: 10.3390/org6020019

Authors: Carlo Santulli Serena Gabrielli Graziella Roselli

Most bioplastics are based on polysaccharides, which are either synthesized from a variously sourced monomer or extracted from some biomass waste. In many cases, some lignocellulosic fibers are then added to the obtained bioplastics to form biocomposites and extend their range of applications beyond packaging films and generically easily biodegradable materials. Plant-extracted tannins, which, as such, might also be building blocks for bioplastics, do nonetheless represent a useful complement in their production when added to polysaccharide-based plastics and biocomposites, since they offer other functions, such as bioadhesion, coloration, and biocidal effect. The variety of species used for tannin extraction and condensation is becoming very wide and is also connected with the local availability of amounts of bio-waste from other productions, such as from the food system. This work tries to summarize the evolution and recent developments in tannin extraction and their increasing centrality in the production of polysaccharide-based plastics, adhesives, and natural fiber composites.

Organics doi: 10.3390/org6020018

Authors: Bálint Jávor Antal Agárdi Péter Kisfaludi Barnabás Frigyes Márton Temesvári Panna Vezse Tünde Tóth Péter Huszthy Ádám Golcs

Bipyridine ethers are commonly occurring structural motifs in supramolecular chemistry. The herein reported efforts aim to extend the synthetic platform of bipyridino-precursors with new bifunctional intermediates and to improve some previously reported synthetic strategies for structural analogues, like bipyridine-diols as common macrocycle precursors. In addition, their optimized and highly efficient oxidation to the corresponding dialdehydes is reported to obtain further reactive intermediates with wide modifiability. Furthermore, methylations of pyridine-carbaldehydes were carried out alongside different synthetic strategies to introduce chirality centers. Synthetic difficulties and some unsuccessful approaches are also reported to help in focusing future efforts.

Organics doi: 10.3390/org6020017

Authors: Danijela S. Kretić Marija I. Maslarević Dušan Ž. Veljković

Understanding the factors that affect the detonation performance of high-energy molecules (HEMs) is crucial for the design of novel explosives and fuels with desirable characteristics. While molecular factors, such as the presence of specific functional groups that give organic molecules explosive properties, are key determinants of detonation characteristics, other factors like the geometry of molecules in crystal structures can also affect the high-energy properties of materials. Although it is known that slight deviations in the crystal structure geometry affect the sensitivity of nitroaromatic explosives, the influence of these variations on detonation performance remains unknown. In this study, we extracted different crystal structures of the same high-energy nitroaromatic molecules from the Cambridge Structural Database and calculated their detonation velocities and pressures using the Kamlet–Jacobs equations. Results indicated that different geometries of the same crystal structure can lead to non-negligible differences in detonation velocities and pressures. In the case of the 2,4,6-triamino-1,3,5-trinitrobenzene molecule, discrepancies in detonation pressures among different crystal structures were calculated to be 7.68%. Analysis of geometrical arrangements showed that these differences are mainly the consequence of diverse non-covalent bonding patterns that affect crystal densities.

Organics doi: 10.3390/org6020016

Authors: Ayoub El-mrabet Amal Haoudi Youssef Kandri-Rodi Ahmed Mazzah

Quinolones represent one of the largest classes of synthetic antibiotics used in both human and veterinary medicine. Since the discovery of nalidixic acid, a substantial body of research has been carried out on quinolones, resulting in the synthesis of several quinolone derivatives with exceptional pharmacology. In addition to their antibacterial action, quinolones have a broad spectrum of diverse biological activities. In this regard, the present review examines the literature of recent years describing synthesis protocols, reactivity and biological properties, with particular emphasis on the antibacterial, antimalarial, antitrypanosomal, antileishmanial, antiviral and anticancer activities of this famous class of molecules. Finally, this review highlights the potential of quinolones as preferred pharmacophores in medicinal chemistry. The aim is to highlight the innovative aspects of the rational design of new therapeutic agents with this structural motif, in the face of emerging antibiotic resistance and the urgent need for new active molecules.

Organics doi: 10.3390/org6020015

Authors: Marcello Casertano Brian G. Kelly Malachi W. Gillick-Healy Paolo Grieco Mauro F. A. Adamo

Indole heterocycles have an established reactivity, and these compounds are H-bond donors via a peculiar non-basic NH. However, the indole core has been scarcely employed in organocatalysis, with only a few examples relevant to electrophilic halogenation reported. To expand the range of potential transformations achievable via indole catalysis, we have designed a set of new organic species incorporating an indole core, alongside three privelaged chiral moieties found in many known organocatalysts, namely a quaternary ammonium salt, a diamine and an amino-urea. Herein, we report an optimised synthetic route for the preparation of these potential catalytic species in an enantiomerically pure form. The syntheses are conceived to be modular and therefore will allow each of the three single organic catalysts to be expanded into families without alteration of the synthetic layout, therefore leading to a fast optimisation of new asymmetric procedures.

Organics doi: 10.3390/org6020014

Authors: Alam Yair Hidalgo Quirino Torres-Sauret Carlos Ernesto Lobato-García Erika Madeleyne Ramos-Rivera Luis Fernando Roa de la Fuente Abraham Gómez-Rivera Miguel Ángel Vilchis-Reyes Erika Alarcón-Matus Oswaldo Hernández-Abreu Nancy Romero-Ceronio

This study describes the efficient synthesis of five dinitrochalcones (DNCHs) using an ultrasonic bath as an unconventional method to improve reaction yields and reduce reaction times. The Claisen–Schmidt condensation of nitroacetophenones and nitrobenzaldehydes was carried out in a cyclohexane–methanol solvent system under ultrasonic irradiation, achieving yields between 56% and 92%. The application of ultrasound not only accelerated the reaction but also improved the overall efficiency compared to conventional methods such as magnetic stirring. The synthesized compounds were characterized by NMR spectroscopy, which corroborated their structures. Therefore, it is confirmed that obtaining DNCHs with a nitro group in ortho by ultrasonic irradiation is an energetically efficient and environmentally friendly alternative.

Organics doi: 10.3390/org6020013

Authors: Zuleyma Martínez-Campos Luis Eduardo Hernandez-Dominguez Fatima Romero-Rivera Diana López-López María Vicky Corona-González Susana T. López-Cortina Francisco José Palacios-Can Rodrigo Said Razo-Hernández Mario Fernández-Zertuche

γ-amino butyric acid (GABA) is an inhibitory neurotransmitter whose deficiency has been associated with various neurological disorders. However, its low liposolubility limits its use as a supplement. Thus, multiple investigations have focused on searching for lipophilic GABA analogs that can modulate the activity of the GABAB receptor, which could be associated with the etiology of some central nervous system disorders. The GABA analogs available on the market are Vigabatrin, Gabapentin as well as Pregabalin and Baclofen. In this work, we report on the synthesis of GABA analogs, taking the scaffold of GABA, Pregabalin, and Baclofen as a starting point. The analogs include structural features that could favor the affinity of the molecules for the GABAB receptor, such as heterocyclic rings in the γ-position and alkyl or p-Cl-phenyl substituents (in analogy to Pregabalin and Baclofen, respectively). These analogs were synthesized by a sequence of reactions involving an N-alkylation, a 1,4-conjugated addition of dialkyl and diarylcuprates and a basic hydrolysis. Furthermore, a computational molecular docking over the GABAB receptor was performed to evaluate the interaction of each compound in the Baclofen binding site. With this information, we evaluated our compounds as GABAB agonists through a QSAR analysis. Finally, by means of molecular similarity analysis, and in silico ADME prediction, we support our three best compounds (8a–b, 8d) as potential GABAB receptor agonists.

Organics doi: 10.3390/org6010012

Authors: Mengying Kou Kanshe Li

A graft reaction of polyvinyl chloride (PVC) with furfural was conducted in a tetrahydrofuran solution. The resulting graft structure (FF-g-PVC) was characterized using UV spectroscopy, photoluminescence (PL), Fourier Transform Infrared (FTIR) spectroscopy, Raman spectroscopy, and proton nuclear magnetic resonance (1H NMR) spectroscopy. The grafting efficiency was determined through ultraviolet spectrophotometry. Thermal stability analysis via thermogravimetric (TG) testing revealed that furfural was successfully grafted onto the PVC chain. In a nitrogen atmosphere, the temperature of the maximum weight loss rate during the first stage of pyrolysis increased from 296.3 °C to 301.7 °C, while the activation energy for the second stage increased from 199.4 kJ/mol to 294.4 kJ/mol, indicating enhanced stability and delayed degradation of the PVC. Additionally, microwave irradiation markedly improved the graft reaction, achieving a grafting rate of 57.76‰ compared to only 1.808‰ with water bath heating. The optimal conditions were found to be a PVC/FF/Zn ratio of 1:1:0.9, with microwave irradiation for 20 min at 40 °C.

Organics doi: 10.3390/org6010011

Authors: Chamseddine Derabli Noureddine Rahim Roumaissa Djaba Sarra Aouidi Chawki Bensouici Stephanie Hesse Houssem Boulebd

Six secondary amine derivatives derived from salicylaldehyde (SA) were successfully synthesized in good to excellent yields and evaluated for their biological activities. The synthesized compounds exhibited remarkable antioxidant properties, as determined by ABTS and phenanthroline assays. Notably, compound 2 demonstrated an IC50 value of 5.14 ± 0.11 µM in the ABTS assay, approximately six to nine times lower than the standards BHT and BHA. In the phenanthroline assay, all compounds showed inhibition capacities five to ten times greater than BHT and comparable to BHA, with A0.5 values ranging from 9.42 to 31.73 µM. Among these, compound 5 displayed the lowest A0.5 value of 9.42 ± 1.02 µM. The anti-inflammatory activity, assessed through BSA denaturation, revealed that compounds 2 and 5 were the most promising, although their activity was moderate compared to the standard diclofenac. The insecticidal potential of the compounds was evaluated against the storage insect pest Tribolium castaneum. Among the tested derivatives, compounds 1 and 6 exhibited the highest efficacy, achieving maximum mortality rates of 73.31% and 76.67%, respectively, over a seven-day treatment period. Furthermore, the molecular geometry, electronic properties, and intramolecular interactions of all compounds were investigated using DFT calculations. Thermodynamic analyses of the antioxidant mechanisms suggested that the NH bond is the most likely site for free radical attacks. These findings underscore the significant biological potential of the synthesized salicylaldehyde-derived secondary amines.

Organics doi: 10.3390/org6010010

Authors: Valeria Gagliardi Jesús Castro Valentina Beghetto María Expósito Marco Bortoluzzi

The commercial flame-retardant 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) was almost quantitatively converted in sodium [2-(2-hydroxyphenyl)phenyl]phosphinate Na[OH-Ph-Ph-PHO2] and disodium 2-(2-phosphinatophenyl)benzen-1-olate Na2[O-Ph-Ph-PHO2] under mild reaction conditions and without the use of toxic reactants. The structure of Na[OH-Ph-Ph-PHO2] was determined by means of single-crystal X-ray diffraction. The inter- and intramolecular Na-O interactions generate a stair-like framework where the sodium cations are five-coordinated and exhibit a highly distorted coordination sphere. The two compounds are characterized by appreciable blue luminescence at the solid state upon excitation with UV light, attributed to S1→S0 decays on the basis of time-resolved measurements and computational calculations. The photoluminescence quantum yield is higher for Na2[O-Ph-Ph-PHO2], and the emission and excitation bands are shifted at longer wavelengths. The disodium salt showed affinity towards cellulose, and doped Na2[O-Ph-Ph-PHO2]@cellulose samples maintained emission features comparable to those of the pure compound. The nature of the interaction between cellulose and the emitting species was studied by means of periodic density functional theory calculations, that highlighted the role of the sodium cations.

Organics doi: 10.3390/org6010009

Authors: Madyan A. Yaseen Michael Oelgemöller

A series of photoacylations of 1,4-naphthoquinone with various aldehydes and using Pyrex-filtered UVB light was conducted under continuous-flow conditions. Acetone served as a triplet photosensitizer and convenient solvent that kept all materials in solution and could be easily removed. The corresponding acylated 1,4-naphthohydroquinone photoproducts were obtained in acceptable to excellent yields of 30–90% with residence times of just 70 min. The photoacylation process was successfully coupled with in-line oxidation to obtain acylated 1,4-naphthoquinones.

Organics doi: 10.3390/org6010008

Authors: Amanda Neves de Souza Adriano Monteiro de Castro Pimenta Rodrigo Moreira Verly

Bioactive peptides are promising therapeutic agents due to their antimicrobial and anticancer activities, although their lack of selectivity often limits clinical applications. This study demonstrates the optimal synthetic route for conjugating folic acid (FA) with the bioactive peptide Lunatin-1, aiming to improve selectivity for neoplastic cells. The synthesis combines solid-phase peptide synthesis (SPPS) and Cu(I)-catalyzed cycloaddition to link folic acid to Lunatin-1 via a triazole ring. Using the model tripeptide FIG-NH2, key intermediates and the final product were characterized by high-performance liquid chromatography (HPLC), mass spectrometry (MALDI-ToF), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR). Reaction yields and purity were optimized with FIG-NH2, providing a reproducible synthesis pathway. Additionally, the results confirmed successful conjugation, with the FA-Trz-Luna product exhibiting molecular integrity and structural stability, as validated by spectral analyses. This study highlights a potential synthesis route for peptide-folate conjugates to be used as selective and multifunctional therapeutic agents, laying the groundwork for biological evaluations of their cytotoxicity and antimicrobial properties.

Organics doi: 10.3390/org6010007

Authors: Aleksei E. Machulkin Stanislav A. Petrov Maria D. Kraynova Anastasiia S. Garanina Bayirta V. Egorova Roman V. Timoshenko Alexander N. Vaneev Alexander S. Erofeev Anna B. Priselkova Mikhail A. Kalinin Aleksei V. Medved′ko Stepan N. Kalmykov Elena K. Beloglazkina Sergey Z. Vatsadze

Nowadays, PSMA ligands are widely used for radiotheragnostic purposes in prostate cancer. The synthesis of a PSMA-Bisp conjugate was developed and realized with good yield (overall yield ~58% for the last two steps). All newly synthesized compounds were characterized by physicochemical methods: 1H and 13C NMR, HRMS, and LCMS (for biologically tested samples). Subsequently, Bisp1 (diacetate bispidine ligand), Bisp-alkyne (bifunctional derivative of Bisp1), and its conjugate PSMA-Bisp were labeled by 64Cu in mild conditions. In vitro studies of the labeled conjugate [64Cu]Cu-PSMA-Bisp have shown great stability in model solutions. Finally, [64Cu]Cu-PSMA-Bisp was compared to the well-known PSMA-617 conjugate labeled with 64Cu and they showed similar stability in excess bovine serum (BVS), and at the same time, labeling PSMA-Bisp with 64Cu is characterized by extremely high kinetics in mild conditions, while labeling PSMA-617 with 64Cu requires heating (90 °C). Thus, this conjugate can be incredibly promising for nuclear medicine.

Organics doi: 10.3390/org6010006

Authors: Pedro Freitas Dina Maciel Jolanta Jaśkowska Kamila Zeńczak-Tomera Yanbiao Zhou Guoyin Yin Ruilong Sheng

Developing new biomolecule–drug conjugates as prodrugs is a promising area for natural products and pharmaceutical chemistry. Herein, a cholesterol–doxorubicin (Chol-DOX) conjugate was synthesized using cholesteryl-4-nitrophenolate as a facile, stable, and controllable activated ester. This approach offers an alternative to the conventional HCl-emitting cholesteryl chloroformate method. Semi-empirical theoretical calculations showed that cholesteryl-4-nitrophenolate exhibits moderate reactivity, greater thermodynamic stability, a higher dipole moment, and a lower HOMO-LUMO energy gap compared to cholesteryl chloroformate, suggesting that cholesteryl-4-nitrophenolate could be used as a more controllable acylating agent. The structure of the synthesized Chol-DOX conjugate was characterized using NMR, MS, and FT-IR techniques. Biological properties of the Chol-DOX conjugate were analyzed with a comparison of theoretical and experimental data. This work provides a facile and controllable method to synthesize natural lipid–DOX prodrugs and offers an in-depth data analysis of the related biological properties.

Organics doi: 10.3390/org6010005

Authors: Maria S. Ledovskaya Vladimir V. Voronin Anna A. Reznichenko Ekaterina A. Reznichenko

In this work, we developed a highly efficient and versatile environmentally benign methodology for the vinylation of a broad scope of substances, including alcohols, thiols, and nitrogen compounds. The key advantage of the proposed method is the use of calcium carbide as a robust acetylene source in a stoichiometric ratio to the substrates. Lacking the requirement of acetylene excess, the developed protocol is safe, highly economic, and limits waste production. The procedure allows for a large variety of O-,S-,N-vinyl compounds to be synthesized in up to quantitative yields. Our methodology is scalable, allowing us to obtain vinyl derivatives in Gram-scale quantities. We also demonstrated the significant synthetic value of our approach by performing a label-economic synthesis of 13C2-labeled vinyl derivatives using calcium carbide-13C2. In our well-optimized process, the conversion of Ca13C2 reached 89%.

Organics doi: 10.3390/org6010004

Authors: Rostislava Angelova Georgi Stavrakov

Ferrocene is an organometallic compound that has attracted considerable scientific interest due to its unique properties, including low toxicity, excellent stability in aqueous and aerobic media, and high lipophilicity, which enhances membrane permeability. The ferrocene moiety has been effectively used as a bioisostere of phenyl rings and heteroaromatic groups in the structures of approved tyrosine kinase inhibitors and histone deacetylase inhibitors (HDACis). HDACis exert their cytotoxic effects by blocking cyclin/CDK complexes, causing cell cycle arrest, inducing apoptosis, inhibiting angiogenesis, and through non-histone-directed mechanisms. This mini-review summarizes the synthesis and biological evaluation of small libraries of compounds in which a ferrocenyl moiety is incorporated into the structure of suberoylanilide hydroxamic acid (SAHA) and a number of analogues. The influence of the organometallic function on the antiproliferative effect is investigated. Both docking analysis and in vitro studies confirm that the ferrocenyl-modified HDACis exhibit potent cytotoxicity and strong inhibitory activity against the various enzyme isoforms.

Organics doi: 10.3390/org6010003

Authors: Mukund Jha Dani Youssef Haley Sheehy Amitabh Jha

Heterocyclic compounds are the cornerstone for active pharmaceutical ingredients. Among heterocycles, isoindoline core occupies a special place, as ten commercial bioactive compounds/drugs contain this skeleton decorated with several functional groups required for optimal receptor binding. These drugs are employed for indications such as multiple myeloma, leukemia, inflammation, hypertension, edema, obesity, and insect control. This review presents the pharmacological activities, mechanisms of action, and chemical syntheses of these commercial bioactive molecules/drugs.

Organics doi: 10.3390/org6010002

Authors: Marija Popović-Nikolić Gordana Popović Slavica Oljačić Katarina Nikolić

The acid–base equilibria of cetirizine were investigated with and without the presence of differently charged micelle-forming surfactants (anionic, cationic, nonionic). The pKa values were potentiometrically determined at 25 °C and at a constant ionic strength (0.1 M NaCl). Experimental data were analyzed by applying the computer program Hyperquad 5.2.15. Based on a shift in the ionization constants (∆pKa) in micellar solutions against the pKa values determined in “pure” water under the same conditions, the effects of micelles on the protolytic equilibria of cetirizine were estimated. Applied micelles caused a shift in the protolytic equilibria of all cetirizine ionizable centers, with the piperazine function connected to aliphatic side moiety (∆pKa1 from −0.47 to +1.42), carboxyl group (∆pKa2 from −0.92 to +2.02), and piperazine nitrogen connected to phenyl rings (∆pKa3 from −2.01 to +2.19). Anionic SDS and nonionic Brij 35 micelles caused an increase in the pKa values of the ionizable centers of cetirizine, while a decrease in the pKa values was detected under the influence of cationic CTAB and nonionic TX-100 micelles. The change in the ionization pattern by micelles at pH values with biopharmaceutical significance provides indications of possible interactions of cetirizine with biomolecules of different charge and polarity under physiological conditions.

Organics doi: 10.3390/org6010001

Authors: Oussama Baaloudj Laura Scrano Sabino Aurelio Bufo Lee-Ann Sade Modley Filomena Lelario Angelica Rebecca Zizzamia Lucia Emanuele Monica Brienza

Heterocyclic pharmaceuticals are emerging contaminants due to their toxic, carcinogenic nature and detrimental impact on the natural ecosystem. These compounds pose a significant environmental concern given their widespread use in medical therapy, constituting over 90% of new medications. Their unique chemical structure contributes to their persistence in various environmental matrices, necessitating urgent measures to mitigate their risks. This review comprehensively examines the sources, environmental fate, toxicity, and long-term risks associated with heterocyclic pharmaceuticals, proposing potential remediation strategies. The article commences with an overview of the diverse types of heterocyclic pharmaceuticals and their applications, focusing on compounds containing heteroatoms such as nitrogen, oxygen, and sulfur. Subsequently, it explores the sources and pathways through which these pollutants enter the environment, including wastewater discharge, agricultural runoff, improper disposal, resistance to biodegradation, and bioaccumulation. The toxic effects and long-term consequences of exposure to heterocyclic pharmaceuticals are then discussed, encompassing neurotoxicity, genotoxicity, mutagenesis, cardiovascular and metabolic toxicity, carcinogenicity, and teratogenesis. Additionally, this review summarizes various remediation strategies and treatment solutions aimed at reducing the environmental impact of these compounds, drawing insights from the literature. The research concludes by identifying critical areas for future research, emphasizing the urgent need for more effective remediation strategies to address the growing concern posed by these emerging contaminants.

Organics doi: 10.3390/org5040035

Authors: László Kiss Péter Szabó

Various organic compounds susceptible to anodic polymerization were selected to study the effects of two solvents: acetic acid and ethyl acetate. Phenol and most of its derivatives, as well as resorcinol and 3,5-dihydroxybenzoic acid, exhibited typical electrode deactivation similar to other solvents; however, a continuous decrease in peak currents was not observed for 4-tert-butylphenols or salicylic aldehyde. Similar behavior was noted for monomers unrelated to phenols. In general, peaks were observed only for certain compounds and not in the initial voltammogram. Significant differences between the two solvents were observed in the subsequent voltammetric curves for some monomers. Microelectrode studies using 4-methoxyphenol as a model compound revealed notable differences between acetic acid and ethyl acetate in terms of curve shapes and the onset potentials of the plateaus. Plateau currents were used to estimate the solvent composition, demonstrating relatively high sensitivity to the acetic acid content.

Organics doi: 10.3390/org5040034

Authors: Aliya Yelshibay Sherif Dei Bukari Bakhytzhan Baptayev Mannix P. Balanay

The pursuit of sustainable energy sources has led to significant advances in solar cell technology, with conducting polymers (CPs) emerging as key innovations. This review examines how CPs improve the performance and versatility of three important types of solar cells: dye-sensitized solar cells (DSSCs), perovskite solar cells (PSCs), and organic solar cells (OSCs). Polymers such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene) have shown significant potential to increase the efficiency of solar cells. In DSSCs, conducting polymers act as counter electrodes, electrolytes, and dyes, contributing to improved efficiency and stability. In PSCs, they serve as hole transport materials and electron transport materials that improve charge separation and reduce recombination losses. In OSCs, conducting polymers act as HTMs and active layers, significantly impacting device performance and enabling advances in both binary and ternary solar cell configurations. Recent research highlights the important role of conducting polymers in improving both the efficiency and stability of solar cells under different indoor and outdoor lighting conditions. Recent advances have led to impressive energy conversion efficiencies, particularly in low-light environments. This report also highlights the environmental and economic benefits associated with these materials. At the same time, it highlights the challenges associated with optimizing the materials, scalability, and ensuring long-term stability. Future research directions are outlined to overcome these obstacles and promote the commercial viability of next-generation solar technologies.

Organics doi: 10.3390/org5040033

Authors: Mirjana M. Radanović Ljiljana S. Vojinović-Ješić Niko S. Radulović Vidak N. Raičević Vukadin M. Leovac Marko V. Rodić

Due to the promising characteristics of aminoguanidine Schiff bases, ongoing research focuses on synthesizing and characterizing different compounds of this class to establish structure–property relationships. However, the pronounced alkalinity of the aminoguanidine residue makes isolating its Schiff bases in neutral form challenging. In the reaction of salicylidene-aminoguanidine ([HL]NO3) with a strong base (NaOH), the partially neutralized product of the formula [HL]NO3∙L·H2O was obtained in the form of single crystals. This compound could be considered a cocrystal in which protonated and neutral forms of the Schiff base coexist. Furthermore, the coordinating properties of [HL]NO3 towards zinc and organotin were investigated, and instead of the expected crystals of complex compounds, a novel polymorph of the ligand was obtained. Additionally, the reaction of [HL]NO3, NH4VO3 and salicylaldehyde was carried out to achieve the condensation of the free NH2-group in the aminoguanidinium fragment, targeting a vanadium(V) complex with tetradentate ligand. However, a purely organic compound containing three salicylaldehyde residues and two imine groups, i.e., C21H18N2O3, was isolated. All the obtained compounds were characterized by elemental and spectroscopic analysis, conductometry and SC-XRD analysis. The data were compared to those of similar structures, and the results provide further insight into the properties of these compounds and their future investigation for potential usage.

Organics doi: 10.3390/org5040032

Authors: Avital Shifrovitch Moran Madmon Tamar Shamai Yamin Avi Weissberg

We developed a selective technique to rapidly measure free chlorine, which is the sum of elemental chlorine (Cl2), hypochlorous acid (HOCl), and hypochlorite (OCl−) in water samples via an electrophilic aromatic substitution reaction hyphenated with liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Sample preparation involved derivatization at 25 °C for 15 min with 3,4,5-trimethoxyphenylacetic acid (TMPAA) in an aqueous solution prior to analysis. Several parameters were evaluated to determine the optimized reaction and for the production of informative MS/MS spectrum of the derivatization product, 2-chloro-3,4,5-trimethoxyphenylacetic acid (Cl-TMPAA). The resulting Cl-TMPAA derivative displayed an informative ESI-MS/MS spectrum characterized by product ions at m/z 232.0142, 200.0245, and 185.0009 from the precursor ion at m/z 259.0379. The linear dynamic range of the method (0.1–10 µg/mL) was fitted to concentration levels relevant to forensic toxicology issues. Compared with other analytical techniques, this newly established LC-MS-based method demonstrated specificity, simplicity, and rapidity. This method enables the detection of free chlorine for forensic investigations in criminal cases.

Organics doi: 10.3390/org5040031

Authors: Natalia Agudelo-Ibañez Sergio Torres-Cortés Ericsson Coy-Barrera Ivon Buitrago Diego Quiroga

The synthesis of indole phytoalexin-like analogs related to alkyl (((1-(4-substitutedphenyl)-3-oxo-3-phenylpropyl)thio)carbonothioyl)-ʟ-tryptophanate 1a–d and the evaluation of their antifungal activity against the phytopathogen Fusarium oxysporum is reported. The target compounds were synthesized in the following two stages: (1) the initial esterification of ʟ-tryptophan, which reacted with trimethyl silane chloride and simple aliphatic alcohols (R = Me, Et) under microwave irradiation (MWI) at 100 °C to obtain the respective alkyl ester 2a–b; (2) the resulting mixture of ʟ-tryptophanates 2a–b with carbon disulfide and (E)-chalcone 3a–b under MWI at 50 °C during 60 min, followed by purification through classical column chromatography (55–76% yields). The products were obtained as mixtures of (S,R) and (S,S) diastereoisomers. An LC-DAD-MS analysis allowed us to establish the ratio of these diastereoisomers, and subsequent DFT/B3LYP-based computational calculations of the NMR 1H chemical shifts suggested that the major diastereoisomer involved an (S,R) absolute configuration, comprising more than 60% of the mixture. The compounds 1a–d were subjected to an antifungal activity test against the phytopathogen F. oxysporum using an amended medium-based assay. Compound series 1 showed inhibition percentages of 80% at the first concentration and IC50 values between 0.33 and 5.71 mM, demonstrating greater potential as antifungal agents compared to other ʟ-tryptophan derivatives like alkyl (2S)-3-(1H-indol-3-yl)-2-{[(1Z)-3-oxobut-1-en-1-yl]amino}propanoate, which presented lower inhibition percentages. In summary, phytoalexin analogs derived from ʟ-tryptophan and (E)-chalcones significantly inhibited the mycelial growth of Fusarium oxysporum, indicating their potential as effective antifungal agents.

Organics doi: 10.3390/org5040030

Authors: Mounir Cherfi Tarik Harit Malika Amanchar Ahlam Oulous Fouad Malek

Pyrazole and tetrazole are among the most important heterocyclic members of the azole family. Over the past decade, these N-heterocycles and their derivatives have demonstrated specific properties that give them potent applications in several fields such as pharmacology, technology, and agriculture. Combining these two azoles in single hybrid architecture has given rise to highly potent molecules in terms of efficacy and specificity, with enhanced and scalable properties. In this context, the present paper deals with the literature of the last 10 years describing the synthesis protocols for pyrazole-tetrazole-based molecules. Their biological activities as well as their energetic properties are also reported.

Organics doi: 10.3390/org5040029

Authors: Mohamed Anannaz Fatiha Tafraout Charaf Laghlimi Rachida Ouaabou Jalal Isaad

A simple approach was developed to efficiently graft diethylene triamine onto polystyrene waste using succinic anhydride as a tracer to remove nitrate anions from aqueous solutions. Infrared spectroscopic data showed characteristic signs at 3395 cm−1 and 1695 cm−1 corresponding to N-H and C=O (ester and amide), confirming the grafting of DETA onto PS. The zeta potential study showed that the PS-Succ-DETA adsorbent had a pHiep of 8.2, and its charge was positive when the pH was lower than the pHiep. Parameters affecting nitrate adsorption, such as dosage, initial concentration, pH, and contact time, were studied. The adsorption data corresponded well to the Langmuir isotherm with an R2 correlation coefficient of 0.998, and the adsorption capacity was found to be 195.65 mg/g. The adsorption kinetics of NO3− ions by PS-Succ-DETA corresponded perfectly to the PS-II model, with an R2 coefficient of 0.999. The negative value of ΔG (−10.02 kJ/mol), ΔH (−18.76 kJ/mol), and ΔS (−28.83 J/K/mol) indicates that NO3- adsorption is spontaneous exothermic and suggests a decrease in randomness at the solid-liquid interface during the adsorption. The mechanism of adsorption of nitrate ions onto PS-Succ-DETA occurs via electrostatic interactions and hydrogen bonds between the NO3− ions and the -NH2 and NH functions of PS-Succ-DETA.