Search Results (361)

Azomethine ylides (AMYs) have a nitrogen–carbon double bond and an electron lone pair on the nitrogen atom. They are essential 1,3-dipoles for [3+2] cycloadditions in the synthesis of pyrrolidine-containing heterocycles. Significant progress in 1,3-diplolar cycloadditions has been made in the construction of novel heterocyclic scaffolds, with efforts to broaden substrate scope, enhance stereoselectivity, and integrate green chemistry principles. This article summarizes double cycloadditions of AMYs derived from amino esters and amino acids for the synthesis of novel polyheterocycles. The design of double cycloadditions through the pot, atom, and step economic (PASE) method to increase the reaction efficiency is discussed. The examples presented in this paper may be applied to the synthesis of biologically active molecules. Full article

Understanding how redox-active ligands coordinate to metal centers of different oxidation states is essential for applications ranging from metal remediation and recycling to drug discovery. In this study, coordination complexes of nickel(II), copper(II), and zinc(II) chloride salts were synthesized by mixing the salts with either arylazoformamide (AAF) or arylazothioformamide (ATF) ligands in toluene or methanol. The AAF and ATF ligands coordinate through their 1,3-heterodienes, N=N–C=O and N=N–C=S, respectively, and, due to their known strong binding, the piperidine and pyrrolidine formamide units were selected, as was the electron-donating methoxy group on the aryl ring. A total of 12 complexes were obtained, representing potential chelation events from ligand-driven oxidation of zerovalent metals and/or coordination of oxidized metal salts. The X-ray crystallography revealed a range of coordination patterns. Notably, the Cu(II)Cl₂ complexes, in the presence of ATF, produce [ATF-CuCl]₂ dimers, supporting a potential reduction event at the copper, while other metals with ATF and all metals with AAF remain in the 2+ oxidation state. Hirshfeld analysis was performed on all complexes, and it was found that most interactions across the complexes were dominated by H…H, followed by Cl…H/H…Cl, with metals showing very little to no interaction with other atoms. Spectroscopic techniques such as UV–VIS absorption, NMR (when diamagnetic), and FTIR, in addition to electrochemical studies support the metal–ligand coordination. Full article

Treatment of N,N-dimethylhydrazinoalkenes with diethylzinc followed by exposure of the resulting ethylzinc amides to high vacuum drives a Schlenck redistribution metalloamination/cyclization to generate the corresponding bis(organozinc) intermediates in excellent conversions. Direct treatment of these with appropriate aryl or vinyl electrophiles in the presence of catalytic PdCl₂ (DPEphos) provides the corresponding arylated or alkenylated pyrrolidines and piperidines with high efficiency. Full article

Four 8-acyl-1-pyrrolidinylnaphalenes are prepared where the acyl group is pivaloyl (6), benzoyl (7), benzyloxycarbonyl (8), and ethyloxycarbonyl (9). Crystal structures for 6–8 show that both the carbonyl and pyrrolidinyl groups are nearly perpendicular to the naphthalene ring. Esters 8 and 9 fluoresce more strongly than ketones 6 and 7. All show some solvatofluoro-chromic emission from a charge-transfer excited state. Calculations suggest that both the acyl and amino groups twist back toward planarity with the naphthalene in the relaxed first singlet excited state. With 8 and 9, co-planarity is within 20°, while with 6 and 7, the carbonyl approaches no closer than 30°. With 6 and 7, the charge-transfer emission is replaced with a shorter wavelength band with more polar solvents. Despite the twisted geometries and steric interference toward planarization, these systems do not show emission from a twisted intramolecular charge-transfer (TICT) state. Full article

Salt stress severely constrains agricultural productivity in arid and semi-arid regions. This study evaluated exogenous proline as an osmoprotector in Physalis ixocarpa Brot. (Mexican husk tomato) under salinity. Germination screening identified 75 mM NaCl as a threshold stress level, reducing germination by 38.9% while maintaining seedling viability. Proline pretreatment (30-min imbibition) at 8 mM restored germination to 78% and fresh weight to control levels under salt stress. In vitro experiments revealed that 8 mM proline enhanced chlorophyll content above salt-stressed controls while reducing root length from 9.72 to 5.08 cm, indicating resource reallocation toward photosynthetic protection. Infrared spectroscopy showed characteristic polysaccharide shifts and bands potentially associated with proline incorporation. Gas chromatography–mass spectrometry metabolomics of stem–leaf extracts revealed salt-induced synthesis of nitrogenous osmolytes (such as long-chain amines) and carbohydrate reorganization from α-D-glucopyranoside to β-D-riboside. Proline treatment restored the original carbohydrate profile while generating pyrrolidine derivatives (2.83%), evidence of active proline metabolism. Phenolic antioxidants (e.g., catechol) present in controls were absent under both salt stress and proline treatment, suggesting that proline’s protective mechanism may operate through metabolic regulation of osmolyte pathways and membrane stabilization rather than inducing phenolic antioxidant synthesis. These findings demonstrate proline’s multifaceted protective mechanisms and support its potential application for enhancing salt tolerance in this crop. Full article

Obesity is a major global health concern associated with increased risks of chronic diseases and mortality. Inhibiting pancreatic lipase, a key enzyme in dietary fat absorption, presents a promising therapeutic approach. This study aimed to evaluate the inhibitory potential of piperidine derivatives (1 and 2) and pyrrolidine derivatives (3–13) against pancreatic lipase (PL) through both enzymatic assays and molecular docking simulations. Among the tested compounds, compound 12 demonstrated the highest PL inhibitory activity with IC₅₀ 0.143 ± 0.001 mg/mL and the strongest binding energy (−8.24 kcal/mol), attributed to extensive hydrogen bonding with Gly76, Phe77, Asp79, and His151. Compounds 10 and 13 also exhibited notable inhibitory activity, attributed to their extensive hydrogen bond network with residues Gly76, Phe77, Asp79, and His151. Particularly the presence and position of hydroxy and carbonyl groups and the length of alkyl side chains critically influenced binding stability and specificity. These findings demonstrate that specific structural modifications in pyrrolidine derivatives significantly affect pancreatic lipase inhibition. Compound 12, with its optimal molecular architecture and interaction profile, stands out as the most promising candidate for further development as an anti-obesity agent, with compounds 10 and 13 offering additional scaffolds for future optimization. Full article

Background/Objectives: This article reports pyrrolidine iminosugars of L-gulose absolute stereochemical configuration that are functionalised via N-alkylation to bear boronate ester and boronic acid pharmacophores. Inclusion of boron pharmacophores has been shown to reduce toxicity profiles of drugs and can expand the range of interactions between drugs and target enzymes. Methods: The synthetic development, detailed spectroscopic analysis, and biological investigation against glycosidase enzymes and cancer cell lines of these novel five-membered ring iminosugars are reported. Results: This family of iminosugars displays selective, moderate-to-weak inhibition (IC₅₀s = 133–501 μM) of β-d-galactosidase (bovine liver) and emerging inhibition of β-d-glucosidases (almond) and (bovine liver). The boronic acid pharmacophore may be suitable for the management of lysosomal storage disorders to support the restoration of biological activity of mutant enzymes via the chaperone-mediated therapy approach. From a structure–activity perspective, the cancer screening revealed slight growth inhibition in a panel of cancer cell lines, with A2780 ovarian carcinoma cells showing the strongest response across all compounds. Beyond the growth inhibition capabilities, the real therapeutic potential of these borylated drugs lies in their switch-on/switch-off activation under BNCT radiotherapeutic conditions. Conclusions: This is an important novel family of drug leads capable of interacting with drug targets via intermolecular and intramolecular interactions, changing shape and electronics. Introduction of organic boron atoms to organic molecules presents significant synthetic and purification challenges, as well as analysis of the equilibria that arise in aqueous systems. We provide a methodology to achieve all this and introduce boron pharmacophores onto carbohydrate scaffolds in a systematic manner to facilitate a more widespread adoption of boron pharmacophores. Full article

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine binding site of NMDA receptors. Herein, systematic modifications of homologous aminobutyl substituted 1,3-dioxanes were conducted in order to identify ligands selectively addressing σ receptors or NMDA receptors. Methods: The first step of the synthesis, i.e., the acetalization of benzaldehyde (7a) or propiophenone (7b) with pentane-1,3,5-triol (6), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols 8 provided various primary, secondary and tertiary amines 14, 16–19, and 24–27. The affinity towards σ₁ and σ₂ receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies. Results: Only the primary amines 14b and 24b derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the N-benzylamines 17 and 18 showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine 17a (K_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (K_i(σ₁) = 154 nM, LLE = 6.72) represent the most promising σ₁ ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Conclusions: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies. Full article

The 1:1 stoichiometric reactions of α-amino isobutyric acid (H₂Aib) and diaminosilanes of the type SiRR′(NR¹R²)₂ (SiMe₂(imidazol-1-yl)₂, SiMe₂(NHnPr)₂, and SiRR′(pyrrolidin-1-yl)₂ with R,R′ = Me,Me, Me,H, Me,Vi, and Et,Et) afforded the pentacoordinate silicon complexes (Aib)SiRR′(HNR¹R²) with the release of one equivalent of HNR¹R². Single-crystal X-ray diffraction analyses confirmed the coordination of the N-donor Lewis base (i.e., imidazole, n-propylamine, and pyrrolidine, respectively) in an axial position of the distorted trigonal-bipyramidal Si-coordination sphere, trans to the carboxylate O atom of the Si-chelating Aib-dianion. The N–H moieties of the adduct-forming Lewis bases are involved in N–H⋯O hydrogen bonds with carboxylate groups of adjacent complex molecules, thus supporting the supramolecular structures of these adducts. The equatorially bound NH group of the Aib-dianion is involved in N–H⋯O hydrogen bonds in most cases, and it gives rise to residual dipolar coupling of the ¹⁴N nucleus with its directly bound atoms C and Si, thus causing characteristic shapes of both the ²⁹Si and ¹³C NMR signals of these two atoms in the solid-state spectra. In contrast to the adduct-formation reactions, the analogous conversion of H₂Aib and SiMe₂(NHtBu)₂ did not afford an amine adduct. Instead, a second equivalent of H₂Aib entered the reaction, and the ionic silicon complex [tBuNH₃]⁺[(Aib)₂SiMe]⁻ was obtained and characterized by crystallography and solution NMR spectroscopy. Full article

Certain foods and specific drugs have been linked to epilepsy in the literature. Here, we query PubMed citations for the co-occurrence of epilepsy with foods and drugs, using a list of 217,776 molecules from the HMDB. Notably, the top associations with epilepsy include approved drugs and drug families, diagnostic markers, inducers, and vitamins. Drugs include fosphenytoin (40%), topiramate (37%), valproic acid (34%), hydantoin (20%), phenytoin (31%), carbamazepine (33%), carbamazepine-10,11-epoxide (40%), trimethadione (31%), gabapentin (14%), pregabalin (11%), flunarizine (7%), fenfluramine (4%), bumetanide (4%), KBr (18%), cannabidiol (14%), clonazepam (22%), nitrazepam (10%), diazepam (7%), lorazepam (6%), midazolam (3%), amobarbital (21%), phenobarbital (16%), flumazenil (7%) allopregnanolone (7%), pregnanolone (6%), epipregnanolone (6%), 3-hydroxypregnan-20-one (6%), and vitamin B6 (6%). Drug families and scaffolds include imidazolidine (18%), succinimide (10%), acetamide (7%), 2-pyrrolidinone (7%), pyrrolidine (6%), tetrahydropyridine (6%), and isoxazole (4%). Investigational compounds include cyano-7-nitroquinoxaline-2,3-dione (5%). Diagnostic markers include exametazime (10%) and quinolinic acid (3%). Inducers include flurothyl (37%), pentetrazol (32%), pilocarpine (25%), (+)-Bicuculline (8%), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP, 6%). Our analysis highlights frequently cited associations between epilepsy and specific drugs and highlights the importance of supplementing nutrients with vitamin B6 and the ketogenic diet, which increases the gamma-aminobutyric acid (GABA)/glutamate ratio. As such, our study offers dietary approaches in the treatment of this neurodegenerative disease. Full article

Fused and spiro nitrogen-containing heterocycles play an important role as structural motifs in numerous biologically active natural products and pharmaceuticals. The review summarizes various approaches to the synthesis of three-, four-, five-, and six-membered fused and spiro heterocycles with one or two nitrogen atoms. The assembling of the titled compounds via cycloaddition, oxidative cyclization, intramolecular ring closure, and insertion of sextet intermediates—carbenes and nitrenes—is examined on a vast number of examples. Many of the reactions proceed with high regio-, stereo-, or diastereoselectivity and in excellent, up to quantitative, yield, which is of principal importance for the synthesis of chiral drug-like compounds. For most unusual and hardly predictable transformations, the mechanisms are given or referred to. Full article

Cuscohygrine (CUS) and hygrine (HYG) are pyrrolidine alkaloids proposed as biomarkers of coca leaf consumption, a culturally accepted practice in some Latin American countries. Differentiating legal coca use from illicit cocaine consumption holds forensic importance. While LC-MS/MS is preferred, GC-MS remains widely used in Latin American toxicology labs due to accessibility. This study critically evaluates the analytical limitations of GC-MS for detecting CUS and HYG in biological matrices. Key parameters—injector temperature (180–290 °C), injection mode (split/splitless), solvent, liner condition, and matrix—were systematically studied. GC-MS showed significant limitations: low-abundance, non-specific fragments (m/z 42, 84, 98, 140) failed to meet the identification criteria in SIM mode. Thermal degradation of CUS to HYG and CUS-d6 to HYG-d3 was observed, especially with splitless injection and aged liners. Matrix effects produced signal enhancement ranging from +29% to +316%, meaning that analyte responses in biological samples were significantly higher than in neat standards, likely due to reduced degradation or adsorption. Although deuterated internal standards (CUS-d6) partially corrected signal variability and matrix enhancement, these corrections were not sufficient to overcome the fundamental limitations of GC-MS, including poor ion specificity and compound instability. These findings support the need for LC-MS/MS-based approaches for reliable alkaloid detection and question the suitability of GC-MS for CUS analysis in forensic toxicology contexts. Full article

Background/Objectives: The development of antitumor agents possessing low toxicity against non-cancerous cells is still a challenge in medicinal chemistry. In this paper, we report the antitumor activity of “hybrid structures” derived from the amino acid taurine. We have synthesized 26 compounds, structures of which were confirmed using NMR, X-ray diffractometry, and other techniques. Cytotoxicity of the obtained compounds has been evaluated using three human cancer cell lines. Pyrrolidine 4p has exhibited the strongest antiproliferative activity against HL-60 cells with an IC₅₀ of 76.7 μM, while IC₅₀ against normal cells was 176.3 μM. Water-soluble derivatives of taurine have been tested for antileukemia activity in mice of the BDF1 line. Compound 4p has been identified as the leading compound, which increases the mean survival time of mice from 40 to 100% as compared to the control group. Together, these results prove that taurine-based hybrid structures can be a promising scaffold for the discovery of potential antiproliferative agents. Full article

Chiral covalent organic frameworks (COFs) hold great promise in heterogeneous asymmetric catalysis due to their designable structures and well-defined chiral microenvironments. However, precise control over the pore size of chiral COFs to optimize asymmetric catalytic performance remains challenging. Herein, we designed a proline-derived dihydrazide chiral monomer (L-DBP-Boc), which was subjected to Schiff-base reactions with two aromatic aldehydes of different lengths, 1,3,5-triformyl phloroglucinol (BTA) and 4,4′,4″-(1,3,5-triazine-2,4,6-triyl)tribenzaldehyde (TZ), to construct two hydrazone-linked chiral COFs with distinct pore sizes (L-DBP-BTA COF and L-DBP-TZ COF). Interestingly, the Boc protecting groups were removed in situ during COF synthesis. We systematically investigated the catalytic performance of these two chiral COFs in asymmetric aldol reactions and found that their pore sizes significantly influenced both catalytic activity and enantioselectivity. The large-pore L-DBP-TZ COF (pore size: 3.5 nm) exhibited superior catalytic performance under aqueous conditions at room temperature, achieving a yield of 98% and an enantiomeric excess (ee) value of 78%. In contrast, the small-pore L-DBP-BTA COF (pore size: 2.0 nm) showed poor catalytic performance. Compared to L-DBP-BTA COF, L-DBP-TZ COF demonstrated a 1.69-fold increase in yield and a 1.56-fold enhancement in enantioselectivity, possibly attributed to the facilitated diffusion and transport of substrates and products within the larger pore, thus improving the accessibility of active sites. This study presents a facile synthesis of pyrrolidine-functionalized chiral COFs and establishes the possible structure–activity relationship in their asymmetric catalysis, offering new insights for the design of efficient chiral COF catalysts. Full article

Chlorella vulgaris, a unicellular microalga with broad industrial applications, is a valuable source of bioactive compounds, including proteins, pigments, and lipids. However, optimizing its growth and metabolite production remains a challenge. This study investigates the potential of angular 6/6/5/6-annelated pyrrolidine-2,3-diones—structurally complex small molecules resembling alkaloids and 13(14 → 8)abeo-steroids—as novel growth stimulants for C. vulgaris. A series of these compounds (20 structurally diverse derivatives, including 7 previously unreported ones) were synthesized and screened for their ability to enhance microalgal growth. Primary screening identified one compound as a promising candidate, significantly increasing algae cell concentration in microplate cultures. Subsequent validation in flask-scale experiments revealed that this candidate induced a 19% increase in protein content at 1 μmol/L, suggesting potential for protein enrichment in algal biomass. Stability studies of the candidate compound revealed its significant hydrolytic degradation in aqueous media. These findings highlight the potential of angular 6/6/5/6-annelated pyrrolidine-2,3-diones as modulators of microalgal metabolism, offering a new avenue for enhancing C. vulgaris biomass quality, particularly for protein-rich applications in the food and feed industries. Full article