Search Results (375)

Pyrrolidinyl-substituted silacyclopentane (CH₂)₄Si(Pyr)₂ and α-amino isobutyric acid (H₂Aib) react with the release of one equivalent pyrrolidine (HPyr) and the formation of the pentacoordinate silicon bis-chelate (Aib)Si(CH₂)₄(HPyr), which features the di-anion of the amino acid as an (O,N)-chelator and one equivalent of pyrrolidine as an additional lone-pair donor. Crystallographic analyses of the chloroform solvate (Aib)Si(CH₂)₄(HPyr)·(CHCl₃), which undergoes a phase transition at 200 K, and a solvent-free modification (Aib)Si(CH₂)₄(HPyr), which features two crystallographically independent molecules of the complex, revealed that the N atom of the HPyr ligand, as well as the carboxylate of Aib, occupy the axial positions in the trigonal bipyramidal Si coordination sphere; the Si–C bonds of the silacyclopentane rest on equatorial sites. For the isolated molecule in a solvent environment, computational analyses revealed that the energy difference between this configuration and the related isomer with an equatorial HPyr and equatorial–axial positioning of the silacyclopentane motif is marginal. In DMSO solution, the adduct (Aib)Si(CH₂)₄(HPyr) decomposed, forming the hexacoordinate Si complex (HAib)₂Si(CH₂)₄ as one of the decomposition products. In a deliberate manner, this compound was accessible from the diethylamino-substituted silacyclopentane (CH₂)₄Si(NEt₂)₂ and H₂Aib with the liberation of diethylamine. (HAib)₂Si(CH₂)₄ features two mono-anions of the α-amino acid as (O,N)-chelators, their carboxylate O atoms are trans-disposed to silacyclopentane, and their NH₂ groups are mutually trans. Full article

The Hoffman–Loffler–Freytag (HLF) reaction is one of the first transformations to achieve remote C(sp³)-H functionalization and simultaneously provide useful building blocks from readily available reagents. Herein, we propose a photochemical protocol for the HLF cyclization, utilizing UVA light as the initiating force under catalyst-free conditions, followed by base-mediated cyclization, in order to synthesize pyrrolidines in a mild and sustainable manner. Full article

Resistance formation and considerable toxicities limit the application of currently available antiparasitic drugs. Thus, new drug candidates are required. Piperlongumine-based cinnamides are promising antiparasitic compounds. In this study, new synthetic cinnamide derivatives with variable halogen substituents (F, Cl, and Br) were prepared and analyzed. They were tested for activity against Toxoplasma gondii and Leishmania major parasites. Considerable activities against T. gondii parasites were observed for certain chloro- and bromo-substituted cinnamides (IC₅₀ = 1.88–2.72 µM), while activities against L. major were less pronounced. Structure–activity relationships were investigated, which revealed notable relations of anti-toxoplasmal activity with the nature of the applied halogen substituents and a preference for chloro- and bromo-substituents in active compounds. In contrast to piperlongumine, the new active compounds have no methoxy substituents anymore and appear to be suitable for advanced antiparasitic studies. Successful docking of selected derivatives into the colchicine binding site of tubulin provided a strong hint at a possible mode of action for these cinnamides (S-scores of −6.075 and −5.993 kcal/mol). In addition, considerable drug-like properties were determined by ADME-T calculations. Thus, in conclusion, new halo-substituted cinnamides with promising activity against Toxoplasma gondii were identified. The selectivity for Toxoplasma parasites can lead to better drugs for the therapy of toxoplasmosis. Full article

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. Full article

A convergent scheme for the preparation of conjugates with the dispiroindolinone-pyrrolidine-thioimidazolone and glutarimide moieties connected via a triazole-containing linker is proposed. Target conjugates were synthesized by azide–alkyne (3+2) cycloaddition reactions between propargylthio-substituted dispiroindolinone-pyrrolidine-imidazolones and an azido-glutarimide derivative. The starting compounds were available isothiocyanates, glycine, substituted benzaldehydes, chloroacetamide, and ethyl acrylate. The key azide–alkyne (3+2) cycloaddition step was carried out using TBTA as a catalyst, achieving >70% product yields. The resulting bifunctional compounds contained a fragment of dispiroindolinone (a p53-MDM2 interaction inhibitor) and glutarimide, a ubiquitin ligase ligand. The obtained dispiroindolinone-glutarimide conjugates were tested for their potential as hetero-PROTAC compounds for p53 reactivation. Individual conjugates showed preferential cytotoxicity against HCT116 colon carcinoma cells (wild-type53) compared to the isogenic HCT116p53^−/− subline. Full article

4-(2-Aminophenyl)-4-oxobutyronitriles in the presence of formic acid (HCOOH) and p-toluenesulfonic acid (TsOH) undergo an unusual rearrangement providing access to a range of 3-(quinazolin-4-yl)propionic acids that have been poorly represented in the literature, with only a few isolated examples known to date. The reaction demonstrates a new route to the quinazoline core through transfer of the nitrile group nitrogen, mediated through the formation of a pyrrolidine cycle. The availability of 4-oxobutyronitrile precursors—2′-aminochacones—provides high variability of substituents in the required positions of product. The transformation is general and can be extended to the preparation of 2-substituted 3-(quinazolin-4-yl)propionic acids through preliminary acylation or to the synthesis of 4-(quinazolin-4-yl)butyric acids. Full article

This study comprehensively analyzed the effects of gamma irradiation (GI) on the flavor profile of aged light-flavor tartary buckwheat Baijiu (LTB) using E-nose, E-tongue, and high-sensitivity headspace–gas chromatography–ion mobility spectrometry (HS-GC-IMS). A total of 30 volatile organic compounds (VOCs) were identified, with concentrations showing significant dose-dependent correlations with GI treatment. Aging alone reduced harsh and pungent VOCs (e.g., 1-propanol, 2-methyl butanoic acid ethyl ester), while GI followed by aging further decreased undesirable compounds (e.g., butanal-D, pyrrolidine) and enhanced beneficial flavor components, such as 1,1-diethoxy ethane-D and butanoic acid propyl ester. Notably, this treatment partially restored 1-propanol, triethylamine, and 2-butanone-M, though their levels remained significantly lower than in newly brewed LTB, achieving a more balanced purity and flavor complexity. The significantly elevated levels of tetrahydrofuran-M/D, 1,1-diethoxy ethane-D, and cyclohexane in GI-treated aged LTB, along with their dose-dependent accumulation patterns, suggest their potential as reliable markers. Multivariate analysis confirmed that all three techniques (E-nose, E-tongue, and HS-GC-IMS) effectively differentiated LTB samples, with strong correlations between E-nose and HS-GC-IMS data, as well as between E-tongue and HS-GC-IMS results. This work provides flavor fingerprints and potential markers for gamma-irradiated LTB identification, while proposing an innovative technical approach for rapid flavor assessment of light-flavor Baijiu. Full article

The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a multiparametric New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, and 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity using high-speed video microscopy and dynamic pixel analysis. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀/locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions, particularly para-chlorination, are associated with comparatively reduced functional separation between these endpoints within the assay. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with comparatively higher cardiac liability within this experimental framework. Full article

(2RS,3aRS,9aRS)-3a-methyl-2-phenyl-3,3a,9,9a-tetrahydro-1H-benzo[f]indol-4(2H)-one hydrobromide was first synthesized via a tandem aza-Cope rearrangement and Mannich reaction from (1RS,2SR)-2-amino-1-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-1-ol, which, in turn, was obtained in four steps from commercially available 2,3-dihydro-1H-inden-1-one. The molecular and crystal structure features of the new compounds were characterized using NMR spectroscopy (¹H, ¹³C spectra). Full article

Enantiopure γ-lactams have emerged as promising scaffolds for anticancer drug development, yet the influence of stereochemistry on their biological activity remains insufficiently explored. In this study, we evaluated the in vitro cytotoxicity and in vivo toxicity of selected enantiopure 3,3-dichloro-γ-lactams and their corresponding epimers, with particular focus on their selectivity toward tumor versus non-tumor cells. The compounds were synthesized through green photoredox processes and tested for cytotoxicity using MTT and NRU assays in human cancer cell lines (A431, HeLa, MCF-7) and non-tumor controls (3T3, HaCaT). Toxicity and tolerability were further assessed in vivo using zebrafish (Danio rerio) embryos. Among the series, compound 3 displayed the most favorable selectivity index, combining potent anticancer effects with reduced activity toward non-tumor cells (HaCaT). Consistent with the in vitro results, compound 3 also demonstrated superior tolerability in zebrafish embryos compared with compound 4. These findings highlight the critical role of stereochemistry in modulating the cytotoxic and safety profiles of γ-lactams. Overall, compound 3 ((R)-3,3-dichloro-4-methyl-1-((S)-1-phenylethyl)pyrrolidin-2-one) emerges as a promising candidate for further preclinical development. Full article

With the advent of new analytical technologies and the urgent environmental problem, reopening investigations into polluting waste matrices becomes a priority. Olive mill wastewater is a pollutant and phytotoxic by-product of olive oil production. An untargeted UHPLC-QTOF analysis of three olive mill wastewaters from three different olive cultivars was performed, and modern informatic platforms were involved to characterize the chemical components in-depth. Data elaboration and statistical analysis confirmed the differences between samples and revealed a total of 364 annotated compounds, including iridoids, phenolic compounds, flavonoids, lignans, cinnamic acid derivatives, and pyrrolidine derivatives. Many of these metabolites, including compounds with known antioxidant and bioactive potential, are scarcely reported in olive products and by-products. The outcomes of this work could be useful for rethinking olive mill wastewater as a source of bioactive compounds to develop and optimize new detoxification strategies. Full article

Halide-dictated stereoselective formation of octahedral Δ-cis-α-[Zn(L)Cl₂] or trigonal bipyramidal Λ-[Zn(L)I]I, where L is a chiral tetramine with a pyrrolidine or piperidine core, has been observed in both the solid state and in solution through a combination of SCXRD analysis, NMR spectroscopy, and theoretical calculations. Chameleonic behaviour is exhibited by the bromido compounds which form five- or six-coordinate complexes depending on the nature of the tetramine ligand. Only six-coordinate Δ-cis-α-[Cd(L)X₂] complexes are observed for Cd(II), irrespective of L or X. Full article

Ten previously undescribed pyrrolidine alkaloids, namely penicipyrrolidines O–X (1–10), were isolated from the mangrove-derived fungus Penicillium sp. DM27, along with five known compounds (11–15). Their structures were determined by comprehensive analysis of HRESIMS and NMR spectroscopic data, and the absolute configurations were established based on biosynthetic considerations and TDDFT-ECD calculations. All isolates were evaluated for their glucose uptake capacity. Notably, penicipyrrolidine P (2) significantly enhanced cellular glucose uptake in L6 myotubes by 3.83-fold, demonstrating activity comparable to that of metformin, whereas penicipyrrolidines Q and R (3 and 4) showed relatively weaker effects. Full article

Background: The synthesis and biological investigation of pyrrolidine (L-gulo) iminosugars bearing an organic boron pharmacophore in ortho and meta positions of an N-benzyl group is reported. This paper completes the structure–activity relationship data for this novel family of boron-bearing iminosugars. These can establish reversible intramolecular interactions via dative bonding from nucleophilic amino acid side chains to the empty p-orbital of the boron atom. Methods: Inhibitory activities against two panels of glycosidases and cancer cell lines were investigated to ascertain structure–activity relationship profiles for these novel iminosugar drug leads. Results: These iminosugars display selective, moderate-to-weak inhibitions (IC₅₀s = 116–617 μM) of β-D-galactosidase (bovine liver), and indications of inhibition of β-D-glucosidases (almond, bovine liver) (IC₅₀s = 633 and 710 μM) and α-D-glucosidases (rice, yeast, rat intestinal maltase) (IC₅₀s = 106–784 μM). The boronic acid group emerges as a useful pharmacophore for management of lysosomal storage disorders via the chaperone-mediated therapy approach. The cancer assays revealed that the A2780 ovarian carcinoma cell line is selectively inhibited by all compounds screened and the MIA-Pa-Ca2 pancreatic carcinoma cell line is selectively inhibited by most compounds. Growth inhibition and GI₅₀ values were most potent for the meta 7 side-product. Conclusions: Beyond the cancer cell line inhibition and dose-response capabilities, the real therapeutic potential of these borylated drugs lies in their switch on/switch off activation under boron neutron capture therapy (BNCT) radiotherapeutic conditions, thus providing an important area of application for borylated monosaccharides. Full article

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