Search Results (440)

The cyclic adamantane framework possesses unique properties such as bulkiness, symmetry, and high lipophilicity. Research aimed at discovering new pharmaceutical agents within the adamantane series continues. In the present work, a targeted modification was carried out to combine two pharmacophore fragments—adamantane and piperidine—within a single molecule. Based on a series of N-substituted piperidin-4-ones, the corresponding secondary alcohols were obtained by reduction with sodium borohydride in isopropanol and subsequent acylation of these alcohols with adamantane carbonyl chloride yielded the corresponding adamantane-carboxylate esters. The structure of the synthesized compounds was studied by NMR methods, including COSY (¹H-¹H), HMQC (¹H-¹³C) and HMBC (¹H-¹³C) techniques. The values of chemical shifts, multiplicities, and integrated intensities of ¹H and ¹³C signals in one-dimensional NMR spectra were determined. The results of COSY (¹H-¹H), HMQC (¹H-¹³C), and HMBC (¹H-¹³C) revealed homo- and heteronuclear interactions, confirming the structure of the studied compounds. The cytotoxic activities of the synthesized compounds were studied. It was found that the synthesized substituted piperidines bearing an adamantane fragment exhibit in vitro antimicrobial and antifungal activity against museum microbial strains (Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538-P, Candida albicans ATCC 10231, Cryptococcus neoformans) and demonstrate significant advantages over the reference drugs used in clinical practice, such as fluconazole and ampicillin. These compounds are therefore recommended for further in-depth studies. Full article

Tandem mass tag (TMT) quantitative proteomic and flavonoid-targeted metabolomic analyses were applied to evaluate the unintended effects of five herbicide-resistant soybean varieties, in addition to three natural genotypic soybean varieties. A total of 65, 29, 56, 38, and 26 differentially expressed proteins (DEPs) were identified in ZLD6010, FD3003, JY2812, ZLD8001, and ZLD2426, respectively, compared with ZH13. Twenty-four and 16 DEPs were identified in ZLD2426 compared with JD12 and KS1, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that most of the DEPs were involved in ribosome, protein processing in the endoplasmic reticulum, and tropane, piperidine, and pyridine alkaloid biosynthesis. Proteomic analysis of the studied soybean seeds revealed no significant changes in herbicide-resistant soybean varieties compared with natural genotypic soybean varieties. Flavonoid-targeted metabolomics analysis detected and quantified 12 flavonoids. Daidzein, genistein/apigenin, taxifolin, and luteolin contents in the herbicide-resistant soybean variety seeds were significantly greater than those in the natural genotypic soybean variety seeds. Their contents in the seeds of three natural genotypic soybean varieties also significantly differed according to pairwise reciprocal comparisons. The introduction of 3-phosphoshikimate 1-carboxyvinyltransferase (EPSPS) might affect flavonoid accumulation of herbicide-resistant soybean varieties. The genetic background of soybean also influences its flavonoid metabolomic profile. Full article

Background/Objectives: Acute pneumonia remains one of the leading causes of mortality worldwide. The pathogenesis of the disease is determined by the nature of the host immune response. The balance between effector and regulatory T cells (Treg) is critical, as it determines the severity of inflammation and the regenerative capacity of lung tissue. The development of new approaches to modulate the immune response using promising synthetic compounds opens up the possibility of targeted cytokine balance restoration of cytokine balance and Tregs functions This study investigated the effects of the newly synthesized complex of 1-(2-Ethoxypropyl)-4-(pent-1-yn-1-yl)piperidin-4-yl Propionate with β-Cyclodextrin (MXF-22), on the populations of CD4⁺, CD4⁺CD25⁺ and CD4⁺FoxP3⁺ T cells in an oleic acid-induced acute lung injury rat model. Methods: Quantitative analysis of CD4⁺, CD4⁺CD25⁺, and CD4⁺FoxP3⁺ T cell subsets and serum IL-4 and TGF-β levels were determined by flow cytometry and ELISA assays, respectively. Results: The study revealed a significant decrease in the number of CD4⁺ T cells and their regulatory subsets (CD4⁺CD25⁺, CD4⁺FoxP3⁺) during acute pneumonia. Oral administration of MXF-22 contributed to a pronounced recovery of these parameters, accompanied by increased levels of IL-4 and TGF-β, which indicated the activation of anti-inflammatory and reparative processes. Conclusions: MXF-22 showed a pronounced immunomodulatory effect contributing to the restoration of the function of CD4⁺ FoxP3⁺ T regs in acute pneumonia rat model. Full article

Species of the Neltuma syn Prosopis genus are known for their use in traditional medicine in America, Asia and Africa. The use of the leaves, bark and inflorescences of one species widely distributed in the arid zones of Mexico, Neltuma laevigata (Humb. & Bonpl. Ex Willd) Britton & Rose, has been reported for the treatment of ocular, gastric and skin infections. Its activities have been related to different secondary metabolites, particularly phenylpropanoids and alkaloids. In the present study, the antibacterial activity of the alkaloidal fraction of inflorescences of P. laevigata collected in Zapotitlán Salinas, Puebla, México, against Staphylococcus aureus ATCC 25,923 and Vibrio cholerae CDBB-1159 was studied by Kirby–Baüer and broth microdilution tests, and its activity on plasmatic membranes was later identified using a protein leakage assay and fluorescence microscopy. Subsequently, the alkaloidal fraction was separated via chromatographic methods, and the purified compounds were elucidated using nuclear NMR and HRESIMS analysis. The alkaloidal fraction showed an important antibacterial activity, with a possible effect on the cytoplasmic membrane of the tested strains. Julifloridine, a piperidine alkaloid previously reported in the genus, was identified for the first time in this species. 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

Tetrakis (Hydroxymethyl) Phosphonium chloride (THPC) in aqueous solution reacts with amines to form aminomethylenephosphines. The reaction was studied with piperidine, and THPC was used with PEI. The reaction with PEI leads to new polymers with phosphine groups (PEI-P) and phosphine oxide (PEI-PO) after oxidation by hydrogen peroxide. These polymers coordinate cations of transition metals, lanthanides and actinides. Full article

Transcriptomic analysis of fruit flesh of the cultivars ‘Trinity’ (red-fleshed) and ‘Free Redstar’ (white-fleshed) uncovered a set of ten genes involved in different metabolic pathways. Three—N3Dioxy, LAR1 and F3Mo—were mapped via phenylpropanoid and flavonoid biosynthesis (mdm00940, mdm00941); four—AlcFARed, CER1, Cyp86A4 and PalmTransf—were mapped on the cutin, suberine and wax biosynthesis pathways (mdm00073); and three—TropRed, CyP865B1 and CytP450—were mapped via the tropane/piperidine/pyridine alkaloid biosynthesis pathway and the peroxisome pathway (KEGG:mdm00960, KEGG:mdm04146). Our study highlighted the higher activity of AlcFARed, CER1, PalmTransf and CYP86A4 in red-fleshed apple fruits and allowed us to discover a specific relationship between significant reductions in fruit wax coating and anthocyanin enrichment in fruit flesh. In addition, the uncovered inhibition of the TropRed gene and the activation of both Cyp865B1 and CYP86A4 suggests that both compounds generate primary alcohols and alkanes, ultimately bound to wax formation. Our results postulate that the fatty acid degradation process is initiated in the flesh of apple fruits and depends on the relationship between anthocyanin content and lipid and wax metabolism. These findings further our understanding of the molecular mechanism linking anthocyanin and wax, making it significantly important in the context of apple fruit storage stability. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose primary manifestation is motor dysfunction. Previous research showed that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremine) exhibits potent antiparkinsonian activity in animal models of PD, with an efficacy comparable to levodopa. Herein, we report the synthesis of a new Prottremine derivative, (1R,2R,6S)-3-methyl-6-(3-(4-phenylpiperidin-1-yl)prop-1-en-2-yl)cyclohex-3-ene-1,2-diol. The compound was fully characterized and its structure was confirmed through single-crystal X-ray diffraction analysis. Full article

Buchenavianine, or 7-hydroxy-5-methoxy-8-(1-methylpiperidin-2-yl)flavone, along with its related compounds O-Demethylbuchenavianine, N-demethylbuchenavianine, and N,O-bis(dimethyl)buchenavianine, belong to the class of piperidine-flavonoid alkaloids, possessing a piperidine ring connected to the C8-position of the flavonoid skeleton. Buchenavianine derivatives have been primarily isolated from Buchenavia macrophylla and also found in B. capitata. Studies have suggested that buchenavianines may possess anti-inflammatory, antioxidant, anti-HIV, and anticancer properties. Understanding the biological activity of buchenavianine derivatives is crucial for assessing their potential as drug candidates, considering factors such as pharmacokinetics and toxicity. The present study focuses on the in silico prediction of antibacterial, antiviral, and antifungal activities using the AntiBac-pred, antiVir-pred, and AntiFun-pred tools available on the Way2drug platform. Results are presented as confidence values indicating the likelihood of inhibitory or non-inhibitory effects against specific pathogens (bacteria, viruses, or fungi). The calculations suggest that the natural buchenavianines under investigation are likely to exhibit antibacterial activity with confidence values ranging from 0.4980 to 0.3390, even against resistant bacterial strains. Antifungal activity was predicted with confidence values of 0.1250–0.0274, while calculations of antiviral activity resulted in high confidence values of 0.8739 to 0.7500, highlighting their potential as antiviral agents. Toxicity assessments of buchenavianine derivatives were conducted using ProTox 3.0 software. The results indicate that all compounds would be non-toxic with a low probability of neurotoxicity and a high probability of respiratory toxicity. Full article

This study reports the solvent-free mechanochemical synthesis of a novel series of 2-hydrazone-bridged benzothiazole derivatives 19–52 via the reaction of 2-hydrazinylbenzothiazole derivatives 4–6 with O-alkylated benzaldehydes 7–18. The stereostructure of the E-isomers was confirmed by 2D NOESY spectroscopy. The antiproliferative potential of these newly prepared 2-hydrazone derivatives of benzothiazole 19–52 was evaluated in vitro against eight human cancer cell lines. Several compounds demonstrated low micromolar IC₅₀ values, with some outperforming the reference drug etoposide. Among the most potent compounds, the 6-chloro-2-hydrazone(3-fluorophenyl)benzothiazole derivative 38 exhibited remarkable activity against pancreatic adenocarcinoma (Capan-1, IC₅₀ = 0.6 µM) and non-small cell lung cancer (NCI-H460, IC₅₀ = 0.9 µM). Structure–activity relationship analysis revealed that derivatives 45–52, featuring a methoxy group at position 6 of the benzothiazole ring and either a methoxy or fluorine substituent at position 3 of the phenyl ring, showed consistently strong antiproliferative effects across all tested cell lines (IC₅₀ = 1.3–12.8 µM). Furthermore, compounds bearing N,N-diethylamino or N,N-dimethylamino groups at position 4 of the phenyl ring generally exhibited superior activity compared to those with morpholine or piperidine moieties. However, as this study represents an initial screening, further mechanistic investigations are required to confirm specific anticancer pathways and therapeutic relevance. In addition to their in vitro anticancer properties, the antibacterial activity of the compounds was assessed against both Gram-positive and Gram-negative bacteria. Notably, compound 37 demonstrated selective antibacterial activity against Pseudomonas aeruginosa (MIC = 4 µg/mL). Overall, this work highlights the efficiency of a green, mechanochemical approach for synthesizing E-isomer hydrazone-bridged benzothiazoles and underscores their potential as promising scaffolds for the development of potent antiproliferative agents. Full article

The reaction of imidazole-5-carbohydrazide 1 with hydrazonyl halides 2a,b gave the corresponding hydrazide–hydrazone derivatives 3a,b. Afterwards, 3-methyl-5-(4-methyl-2-aryl-1H-imidazol-5-yl)-4-(2-phenylhydrazineylidene)-4H-pyrazole 4a,b was affordably produced by cyclizing the latter compounds 3a,b in EtOH with Et₃N at reflux temperature. The corresponding piperidinyl, morpholinyl, and piperazinyl derivatives 5a–f were produced by a nucleophilic substitution reaction of 3a,b with piperidine, morpholine, and 1-methylpiperazine in EtOH at reflux temperature. The condensation reaction of carbohydrazide 1 with either 3-acetyl-2H-chromen-2-one or 1-(benzofuran-2-yl)ethan-1-one in EtOH with AcOH at reflux temperature yielded the corresponding hydrazones 6 and 7, respectively, in excellent yields. Twelve compounds were evaluated for their antibacterial properties and to ascertain their minimum inhibitory concentrations utilizing well diffusion methods. All compounds showed differing levels of antibacterial efficacy depending on the microbial species. Compounds 4b and 5c had the most favorable results, with inhibition zones of 2.7 cm against the Gram-positive bacterium S. aureus, with a minimum inhibitory concentration (MIC) of 50 µg/mL. Compounds 4b and 5c, demonstrating the highest activity, were subjected to molecular docking investigations to evaluate their inhibitory effects on the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase [GlcN-6-P] of 2VF5. The molecular docking results revealed that both 4b and 5c exhibited a minimum binding energy of −8.7 kcal/mol, whereas the natural ligand GLP displayed a binding energy of −6.2 kcal/mol, indicating a substantial affinity for the active site; thus, they may be considered potent inhibitors of GlcN-6-P synthase. 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

Background/Objectives: Lifitegrast is a recent therapeutic agent provoking scientific and regulatory interest due to its outstanding safety profile and high efficacy in the treatment of dry eye disease. Methods: Herein we employ NMR spectroscopy and mass spectrometry to investigate the weak spots of lifitegrast under standard to extreme stress conditions, resulting in the characterization of three known and nine new degradation products (of which DP7 presented the greatest structural challenge, but was eventually determined as C10 hydroxy derivative, warranting a revision of its previously suggested structure). Results: The first weak spot is identified as a N1–C40 amide bond, and its high susceptibility to hydrolysis is explained through computational DFT analysis. The second and third weak spots are elucidated through bond dissociation energy (BDE) calculations which highlighted the oxidative vulnerabilities of both the piperidine and benzofuran ring. Conclusions: Additionally, two degradation products, observed in initial, extended, and targeted oxidative forced degradation studies, were selected for in silico toxicity assessment and were predicted to have toxicity profiles comparable to or lower than lifitegrast. Full article

The giant panda (Ailuropoda melanoleuca) is a vulnerable animal in China, and it is crucial to improve the reproduction efficiency of the giant panda. Mate preference is an important part of natural mating. We hypothesized that AGS metabolites differ according to their mate preference. In this study, we determined estrus-associated hormone levels in the urine of 19 female giant pandas. After confirming estrus via hormone levels and behavioral observation, we collected environmental biomarkers for metabolomics analysis. A total of 19 samples were divided to two groups according to the mating preference of female giant pandas. Metabolomics analysis by LC-MS/MS showed that a total of 115 differentially expressed metabolites were identified, including 97 upregulated metabolites and 18 downregulated metabolites. We found that prostaglandin B2, palmitoylcarnitine, prostaglandin G2, and estrone may be the potential markers of female mate preference. Pathway enrichment analysis showed that steroid hormone biosynthesis, phenylalanine metabolism, and tropane, piperidine, and pyridine alkaloid biosynthesis were the top three pathways. These results revealed the physiological changes in female giant pandas during mate preference trials, providing a perspective for understanding their chemical communication system reliant on anal gland secretions and improving the success rate of natural mating of giant pandas. 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