Search Results (440)

Lepidium meyenii Walp. (black maca, BM) is a traditional Andean crop increasingly studied for its bioactive potential. This work characterized the phytochemical profile and evaluated the antioxidant, antinociceptive, and neuroprotective properties of a lyophilized aqueous extract of BM hypocotyls. UHPLC-ESI-QTOF-MS/MS identified twelve major compounds, including macamides, imidazole alkaloids, sterols, and fatty acid amides. BM showed a moderate total phenolic content but strong electron transfer-based antioxidant activity in CUPRAC and FRAP assays, together with moderate radical scavenging capacity in ABTS and DPPH systems. In ovariectomized rats, BM significantly reduced brain malondialdehyde levels, mitigated oxidative stress, and improved spatial learning during acquisition in the Morris water maze, confirming its neuroprotective effect. Antinociceptive assays (hot plate, cold plate, and tail immersion) further revealed a rapid but transient increase in nociceptive thresholds. This study provides experimental evidence supporting the analgesic effect of black maca. Molecular docking highlighted lepidiline B and campesterol as key metabolites with strong interactions with redox enzymes, the μ-opioid receptor, and the FAAH enzyme, supporting their role in the observed bioactivities. ADMET predictions indicated favorable oral bioavailability, CNS penetration, systemic clearance, and acceptable safety profiles. These results substantiate the role of black maca as a neuroprotective nutraceutical and highlight its promise as a novel source of rapidly acting natural analgesic compounds. Full article

The aim of this work was to prepare new heterodimeric molecules containing pharmacophoric fragments of 3-cyanoquinoline/3-aminothieno[2,3-b]pyridine/3-aminothieno[2,3-b]quinoline on one side and phenothiazine on the other. The products were synthesized via selective S-alkylation of readily available 2-thioxo-3-cyanopyridines or -quinolines with N-(chloroacetyl)phenothiazines, followed by base-promoted Thorpe–Ziegler isomerization of the resulting N-[(3-cyanopyridin-2-ylthio)acetyl]phenothiazines. We found that both the S-alkylation and the Thorpe–Ziegler cyclization reactions, when conducted with KOH under heating, were accompanied to a significant extent by a side reaction involving the elimination of phenothiazine. Optimization of the conditions (0–5 °C, anhydrous N,N-dimethylacetamide and NaH or t-BuONa as non-nucleophilic bases) minimized the side reaction and increased the yields of the target heterodimers. The structures of the products were confirmed by IR spectroscopy, ¹H, and ¹³C DEPTQ NMR studies. It was demonstrated that the synthesized 3-aminothieno[2,3-b]pyridines can be acylated with chloroacetyl chloride in hot chloroform. The resulting chloroacetamide derivative reacts with potassium thiocyanate in DMF to form the corresponding 2-iminothiazolidin-4-one; in this process, phenothiazine elimination does not occur, and the Gruner–Gewald rearrangement product was not observed. The structural features and spectral characteristics of the synthesized 2-iminothiazolidin-4-one derivative were investigated by quantum chemical methods at the B3LYP-D4/def2-TZVP level. A range of drug-relevant properties was also evaluated using in silico methods, and ADMET parameters were calculated. A molecular docking study identified a number of potential protein targets for the new heterodimers, indicating the promise of these compounds for the development of novel antitumor agents. Full article

Background: Cancer remains a leading cause of morbidity and mortality worldwide, and current therapies are limited by toxicity, cost, and resistance. Inhibition of the MDM2–p53 interaction is a promising anticancer strategy, as this pathway is frequently dysregulated across tumors. Spiro-isatin-thiazolidinone derivatives have shown diverse biological activities, including anticancer effects, but require optimization to improve potency and selectivity. The aims were to design, synthesize, and evaluate novel spiro-isatin-thiazolidinone hybrids with enhanced cytotoxicity against cancer cells and reduced toxicity toward normal cells. Methods: Derivatives were designed using molecular docking against MDM2, followed by structural optimization. Cytotoxic activity was evaluated in vitro by MTT assays on human and murine cancer cell lines and pseudo-normal cells. Docking and 100 ns molecular dynamics simulations assessed binding stability, while ADMET properties were predicted in silico. Results: Several derivatives exhibited micromolar cytotoxicity, with compound 18 emerging as the most potent and selective candidate (IC₅₀ 6.67–8.37 µM across most cancer lines; >100 µM in HaCaT). Docking showed a strong affinity for MDM2 (−10.16 kcal/mol), comparable to the reference ligand, and stable interactions in simulations. ADMET predictions confirmed good oral bioavailability and moderate acute toxicity, fully compliant with Lipinski’s Rule of Five. Overall, the newly synthesized spiro-isatin-thiazolidinone hybrids, particularly compound 18, demonstrated potent and selective anticancer activity, favorable pharmacokinetic properties and a good toxicity profile. Full article

The inhibition mechanism and binding properties of four phenolic acids (ferulic acid (FA), p-coumaric acid (CA), gallic acid (GA), and protocatechuic acid (PA)) on xanthine oxidase (XOD) were investigated. All four phenolic acids acted via a mixed inhibition pattern, mainly influencing the hydrophobic regions and secondary conformation of XOD through hydrophobic bonding and hydrophobic association. Molecular dynamics simulations exhibited that the complexes of XOD with FA and CA revealed smaller radii of gyration (Rg) and solvent-accessible surface areas (SASA), along with lower variability in root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF), collectively indicating greater structural stability. FA, CA, and PA significantly reduced uric acid (UA) concentration in the 25–100 μM range. Although GA only reduced UA levels in cell models at 25 μM, this effect was likely due to its larger polar surface area, which limits cellular uptake. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation suggested that these phenolic acids have potential for development. Full article

Background: Chagas disease and leishmaniasis remain public health concerns. Despite the existence of approved medications for the treatment of these diseases, most patients discontinue treatment due to long drug regimens and/or the severe side effects of these drugs. This leads to treatment failure and potential future drug resistance. Therefore, the search for new molecules with trypanocidal activity, low cytotoxicity, and high selectivity is essential to address this challenge. Methods: In this work, three series (a, b, and c) of pyridine-2,5-dicarboxylate esters were synthesized using different β-keto-esters bearing naturally occurring fragments and 1,2,3-triazine-1-oxides via the inverse electron demand Diels–Alder (IEDDA) reaction. The structural elucidation of the compounds was performed using NMR (¹H and ¹³C) and HRMS, and the crystal structure of compound 6a was also obtained. Furthermore, a biological assay was performed for all synthesized and characterized compounds to determine their cytotoxicity against Trypanosoma cruzi, Leishmania mexicana, and the J774.2 macrophage cell line. Finally, the in silico determination of their pharmacokinetic and toxicological properties was performed using the SwissADME and ProTox 3.0 platforms. Results: Compounds 3a, 4a, 5a, 4b, and 8c had the highest anti-Trypanosoma cruzi activity against both strains (IC₅₀ ≤ 56.68 µM). Compounds 8b, 10a, 9b, and 12b had considerable leishmanicidal activity against Leishmania mexicana against both strains (IC₅₀ ≤ 161.53 µM). Furthermore, in silico prediction of ADMET properties suggest that these pyridine compounds possess good pharmacokinetic profile. The results are also consistent with low in vitro cytotoxicity and high selectivity. Conclusions: The synthesized pyridine-2,5-dicarboxylate esters have promising activity against Trypanosoma cruzi and Leishmania mexicana, with low cytotoxicity and good drug-like properties, suggesting that these compounds are potential candidates for further evaluation as new treatments for Chagas disease and leishmaniasis. Full article

In a continued search for novel plant-based therapeutics with multi-target pharmacological potential, the medicinal plant Dischidia bengalensis (Apocynaceae) was investigated for the first time for its anti-inflammatory, analgesic, and thrombolytic properties, addressing critical therapeutic areas such as rheumatoid arthritis, acute pain, and thrombosis. The methanolic extract and solvent fractions (dichloromethane, n-hexane, and ethyl acetate) were evaluated through integrated in vivo, in vitro, and in silico approaches. Phytochemical screening and GC–MS profiling revealed a diverse array of bioactive constituents, including fatty acids, terpenoids, and phenolic derivatives, many of which are reported to exhibit pharmacological activities. In vivo assays demonstrated that the methanolic extract (400 mg/kg) markedly suppressed carrageenan-induced paw edema (92.31% inhibition) from the 2nd to 4th hour (p  <  0.05, p  <  0.01), while the n-hexane fraction produced the most pronounced analgesic response in both writhing and tail-immersion models (p  <  0.001). Furthermore, the methanolic extract displayed significant thrombolytic activity (33.38  ±  4.27% at 20 mg/mL, p < 0.001) in human blood clot lysis, suggesting potential application in cardiovascular disorders. The scientific novelty of this study was further underscored by in silico molecular docking, ADME/T, and PASS prediction studies. Key bioactive compounds, identified by GC-MS, showed strong binding affinities and promising drug-like properties against pivotal human targets such as TNF-α (PDB: 2AZ5), COX-2 (PDB: 6COX), and tissue plasminogen activator. These findings conclusively establish D. Bengalensis as a promising and novel source of lead compounds for the development of novel therapeutics against inflammatory, pain-related, and cardiovascular disorders. Full article

Type 2 diabetes mellitus (T2DM) remains a global health challenge, prompting the development of novel α-glucosidase inhibitors (AGIs) to regulate postprandial hyperglycemia. This study reports the design, synthesis, and evaluation of indole-based Schiff base derivatives (4a–j) bearing a fixed methoxy group at the C₅ position. This substitution was strategically introduced to enhance lipophilicity, electronic delocalization, and π-stacking within the enzyme active site. Among the series, compound 4g (3-bromophenyl) exhibited the highest inhibitory activity (IC₅₀ = 10.89 µM), outperforming the clinical reference acarbose (IC₅₀ = 48.95 µM). The mechanism was supported by in silico analyses, such as the Density Functional Theory (DFT), molecular electrostatic potential (MEP) mapping, and molecular dynamics simulations, and CNN-based docking revealed that 4g engages in stable hydrogen bonding and π–π interactions with key residues (Asp327, Asp542, and Phe649), suggesting a potent and selective mode of inhibition. In silico ADMET predictions indicated favorable pharmacokinetic properties. Together, these results establish C₅–methoxy substitution as a viable strategy to enhance α-glucosidase inhibition in indole-based scaffolds. Full article

Background/Objectives: Pyrostegia venusta (Cipó-de-São-João), a native Brazilian Cerrado plant, is rich antioxidant phytochemicals. The efficacy of herbal extracts, particularly their phenolic content and antioxidant potential, is influenced by the extraction method used. This study investigated the effects of two drying methods, hot-air oven drying and freeze-drying, on the antioxidant activity, cytotoxicity, and molecular interactions of aqueous extracts from the flowers and leaves of P. venusta. Methods: antioxidant capacity was assessed using DPPH, FRAP, and Folin–Ciocalteu assays; phenolic profiles were characterized by UHPLC; and cytotoxicity was evaluated via the MTT assay in HaCaT human keratinocyte cells. Additionally, in silico ADMET predictions were conducted to assess pharmacokinetics and potential toxicity, followed by molecular docking to evaluate interactions with the proliferation markers Ki-67 and PCNA. Results: freeze-dried extracts, particularly from the flowers, contained higher concentrations of phenolic compounds and exhibited superior antioxidant activity compared to hot-air oven-dried extracts. UHPLC analysis identified a range of bioactive phenolics including caffeic, chlorogenic, gallic, ferulic, and p-coumaric acids, quercetin, and anthocyanidins such as pelargonidin-3-O-glucoside and peonidin-3-O-glucoside, with distinct compositional differences between leaves and flowers. ADMET analysis revealed generally favorable pharmacokinetic properties for most compounds. Docking simulations indicated that multiple phenolics showed synergistic interactions with Ki-67 and PCNA. Conclusions: our findings highlight freeze-drying as the optimal method for preserving bioactive compounds in P. venusta and support the therapeutic potential of its flower extracts. The evidence supports the notion that the biological effects of P. venusta are driven by synergism among multiple constituents rather than isolated compounds. Full article

Inhibitors of the tyrosine kinase Zap70 are actively searched to improve treatments of lymphoid malignancies and autoimmune diseases associated with an abnormal T-cell response. The natural product withaferin A (WFA) has been characterized as a covalent inhibitor of Zap70 capable of blocking the migration of human T-cells. By analogy, we postulated that other withanolides equipped with a thiol-reactive, α,β-unsaturated ketone may form covalent complexes with Zap70. The hypothesis was tested using a molecular modeling approach with a panel of 12 withanolides docked onto the kinase domain of Zap70. Seven natural products revealed a capability to form stable complexes with Zap70 comparable to that of WFA, including withangulatin A, 4β-hydroxywithanolide E, withaperuvin, and ixocarpalactone A. Withangulatin A surpassed all the other withanolides for its ability to engage an interaction with Zap70 kinase and to form covalent complexes via bonding to the Cys346 residue close to the enzyme active site. The physicochemical and ADMET properties of withangulatin A were analyzed via Density Functional Theory calculations and an analysis of its Fukui function descriptors. The C3 position of the enone moiety was identified as the most reactive (nucleophilic) site of the molecule. Withangulatin A revealed a satisfactory ADMET profile with no major toxicity anticipated. It represents a potential hit to guide the design of Zap70 inhibitors. Full article

Background/Objectives: Malaria is a prominent vector-borne disease, with a high mortality rate, particularly in children under five years old. Despite the use of various insecticides for its control, the emergence of resistant mosquitoes poses a significant public health threat. Acetylcholinesterase (AChE) is a crucial enzyme in nerve transmission and a primary target for insecticide development due to its role in preventing repeated nerve impulses. Recent studies have identified difluoromethyl ketone (DFK) as a potent inhibitor of both sensitive and resistant Anopheles gambiae acetylcholinesterase (AgAChE). This study aimed to identify novel AgAChE inhibitors that could be explored for malaria prevention. Methods: We performed a virtual screening on the PubChem database using a pharmacophore model from difluoromethyl ketone-inhibited AgAChE’s crystal structure. The most promising compound was then subjected to molecular docking and dynamics studies with AgAChE to confirm initial findings. ADMET and agrochemical likeness (ag-like) properties were also analyzed to assess its potential as an agrochemical agent. Results: PubChem18463786 was identified as the most suitable compound from the virtual screening. Molecular docking and molecular dynamics studies confirmed its strong interaction with AgAChE. The ADMET and ag-like analyses indicated that PubChem18463786 possesses physicochemical properties suggesting a high probability of non-absorption in humans and meets the criteria for agrochemical similarity. Conclusions: Our findings suggest that PubChem18463786 is a potential AgAChE inhibitor candidate. After validation through in vitro and in vivo experiments, it could be exploited for malaria prevention and serve as a lead compound for the synthesis of new, more effective, and selective agrochemical agents. Full article

Background/Objectives: The rise in antibiotic resistance presents a serious and urgent global health challenge, emphasizing the need to develop new therapeutic compounds. This study focuses on the design and evaluation of a novel series of hybrid molecules that combine the 2-quinolone and 1,2,3-triazole pharmacophores, both recognized for their broad-spectrum antimicrobial properties. Methods: A library of 29 candidate molecules was first designed using in silico techniques, including QSAR modeling, ADMET prediction, molecular docking, and molecular dynamics simulations, to optimize antibacterial activity and drug-like properties. The most promising compounds were then synthesized and characterized by ¹H and ¹³C NMR APT, mass spectrometry (MS), Fourier-transform infrared (FT-IR) spectroscopy, and UV-Vis spectroscopy. Results: Antibacterial evaluation revealed potent activity against both Gram-positive and Gram-negative bacterial strains, with minimum inhibitory concentration (MIC) values ranging from 0.019 to 1.25 mg/mL. Conclusions: These findings demonstrate the strong potential of 2-quinolone–triazole hybrids as effective antibacterial agents and provide a solid foundation for the development of next-generation antibiotics to combat the growing threat of bacterial resistance. Full article

This study investigates the valorisation of sour orange (Citrus aurantium L.) flowers using supercritical antisolvent fractionation (SAF) with CO₂ as an antisolvent. SAF was applied to selectively recover bioactive compounds from ethanolic extracts, using supercritical CO₂ to induce precipitation. Response Surface Methodology (RSM) was employed to optimize operational conditions across a pressure range of 8.7–15 MPa and CO₂ flow rates of 0.6–1.8 kg/h, at a constant temperature of 40 °C. Pressure showed a statistically significant positive effect on precipitate yield, while higher CO₂ flow rates led to reduced recovery. High-performance liquid chromatography (HPLC) analysis identified naringin (33.7%), neohesperidin (21.6%), and synephrine (9.0%) as the main components of the enriched fractions. SAF enabled the selective concentration of these compounds, supporting its application as a green separation technique. As a complementary evaluation, preliminary in silico predictions of ADMET properties and skin permeability were performed. The results indicated favourable absorption, low predicted toxicity, and limited dermal permeation for the major flavonoids. These findings are consistent with available experimental and regulatory safety data. Overall, the study demonstrates the potential of SAF as an effective green technology for the selective extraction and enrichment of high-value bioactive compounds derived from Citrus aurantium flowers, with promising applications in cosmetic, nutraceutical, and pharmaceutical formulations. Full article

Background: Compound lipophilicity is a fundamental physicochemical property for determining the pharmacokinetic and pharmacodynamic profiles of therapeutic substances. It is successfully used in the early stages of drug candidates’ design and development. Aim: Taking into account the importance of this parameter, we aimed to assess and compare the utility of a hybrid procedure based on calculation methods and an experimental one for rapid and simple estimation of the lipophilicity of selected neuroleptics such as fluphenazine, triflupromazine, trifluoperazine, flupentixol and zuclopenthixol and their potential new derivatives. Methods: Log P values of the studied compounds were predicted by means of different platforms and algorithms: AlogPs, ilogP, XlogP3, WlogP, MlogP, milogP, logPsilicos-it, logP_consensus, logP_chemaxon and logP_ACD/Labs. The experimental determination of lipophilicity was carried out by reverse-phase thin-layer chromatography (RP-TLC) using three types of stationary phases—RP-2F₂₅₄, RP-8F₂₅₄ and RP-18F₂₅₄—and mobile phases consisted of acetone, acetonitrile and 1,4-dioxane as organic modifiers. Results: Our results provide a confident proposal of optimal chromatographic conditions to experimentally determine the lipophilicity of neuroleptic drugs, including new derivatives. Conclusions: Additionally, for the first time, the paper shows the application of selected topological indices in determining lipophilicity factors and other ADMET parameters of neuroleptics and, in the future, the newly synthesized quinoline derivatives of the studied compounds. Full article

Although chlorpromazine is primarily used in psychiatry, it has been shown since its introduction to influence the course of neoplastic diseases. According to the strategy of drug repurposing, chlorpromazine has been successfully tested for its potential antitumor effects on multiple cancer cell lines. This effect is consistent with the overlap of molecular pathways observed for years between schizophrenia and cancer. The main objective of this work was to evaluate the lipophilicity of 17 previously synthesized tetracyclic chlorpromazine analogues exhibiting diverse anticancer and antimicrobial activity using thin-layer chromatography and computational methods. For a compound to become an effective drug, it must have a favorable ADMET profile, which determines its pharmacokinetic properties as a drug candidate. Lipophilicity is one of the key parameters widely employed in designing new bioactive compounds as potential therapeutic agents. In this article, chromatographic plates precoated with silica gel 60 RP-18F₂₅₄ and a mixture of acetone and TRIS buffer were used as the mobile phase. The chromatographic parameter of lipophilicity (R_M0) of the investigated compounds determined by means of the Soczewinski–Wachtmeister formula was useful to obtain the values of the experimental lipophilicity parameter expressed as logP_TLC. The results of logP_TLC were compared with theoretical values of logP obtained using different algorithms (iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, and ClogP). Furthermore, the online platforms, such as SwissADME and pkCSM, allowed the determination of the remaining ADME parameters of the quinoline derivatives of chlorpromazine. The study of lipophilicity and ADME factors enabled confirmation that the tested compounds demonstrated favorable properties. Therefore, they can be considered as promising starting structures for further studies. Full article