Search Results (1,638)

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, while its resistance to treatment continues to represent a major therapeutic challenge. In the present study, a series of phenothiazine derivatives, including hybrids containing a 1,2,3-triazole linker and the zidovudine (AZT) fragment, were synthesized and evaluated for their anticancer activity against colorectal cancer cell lines HCT116 and HT-29 as well as non-cancerous BEAS-2B cells. Cytotoxic activity was determined using the Alamar Blue assay, while the mechanisms of action were investigated by flow cytometric analysis of apoptosis, cell cycle progression, and reactive oxygen species (ROS) generation. Additionally, changes in the expression of genes associated with apoptosis, oxidative stress, and DNA damage response were analyzed by RT-qPCR. The obtained results demonstrated that AZT-containing derivatives exhibited stronger anticancer activity than non-conjugated phenothiazine analogs. Compounds A9–A12 induced pronounced apoptosis and significant disturbances in cell cycle progression, particularly in HCT116 cells. Among the analyzed derivatives, compound A9 displayed the most favorable overall biological profile, combining strong proapoptotic and cytotoxic activity with relatively high selectivity toward cancer cells and moderate effects on non-cancerous cells. The results indicate that molecular hybridization of phenothiazine derivatives with the AZT scaffold represents a promising strategy for the development of novel anticancer agents targeting colorectal cancer. Full article

Background/Objectives: Resistant pathogenic bacteria and fungi are a growing problem worldwide; therefore, the discovery of new active ingredients is an important challenge for which the functionalization of natural terpenes with biologically active heterocycles can provide a basis. To reach this goal, a series of 1,4-disubstituted-1,2,3-triazole conjugates was designed and synthesized starting from commercially available α-santonin. Methods: The key azido derivative intermediate was prepared according to literature procedures via Michael addition between dehydrosantonin and the TMSN₃/AcOH/Et₃N system at its highly reactive α-methylene-γ-lactone motif. Subsequently, the obtained azide was applied to regioselective Huisgen 1,3-dipolar cycloaddition reaction with a wide range of terminal alkynes bearing N-, S- and O-heterocycles. These include pyridine, pyrimidine, purine, quinoline, indol, or coumarin to afford the sesquiterpene–heterocycle chimaeras. All triazole conjugates were screened for in vitro antiproliferative activity by MTT assay against HeLa, MDA-MB231, SiHa, MCF-7 and A2780 human cancer cell lines compared with fibroblast cells (NIH/3T3) to check their cytotoxicity and antimicrobial effects on two Gram-positive (B. subtilis, S. aureus) pathogenic bacteria, two Gram-negative (E. coli and P. aeruginosa) pathogenic bacteria, and two yeasts (C. krusei and C. albicans). Results: The results indicated that most of the examined compounds expressed weak activity against human cell lines, while some of them showed moderate activity against S. aureus (up to 99% inhibition at 100 µg/mL conc.), C. krusei (up to 51% inhibition at 10 µg/mL conc.) and C. albicans (up to 52% inhibition at 10 µg/mL conc.). Conclusions: Further structural modification of the best, selective antibacterial and antifungal compounds may open the possibility to the development of effective natural sesquiterpene-based selective antimicrobial agents. Full article

Dysregulated lipid metabolism is a core pathogenic driver of type 2 diabetes. Honokiol (HKL), the major bioactive constituent of Magnolia officinalis, possesses anti-diabetic and lipid-regulatory properties. However, the underlying molecular mechanism remains elusive. This study investigates how HKL ameliorates high-glucose/high-fat (HGHF)-induced hepatic lipid accumulation, with a focus on the role of SIRT3-mediated deacetylation of peroxisome proliferator-activated receptor γ (PPARG). The core targets of HKL were identified through network pharmacology and molecular docking. Human hepatic MIHA cells were treated with glucose (Glu, 40 mM) and palmitic acid (0.2~0.3 mM PA) to establish a lipid accumulation model, followed by treatment with HKL (5–10 μM) with or without a confirmed selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). Lipid accumulation was assessed by Oil Red O staining and by measuring triglyceride (TG) and total cholesterol (TC) levels. Protein expression and the SIRT3-PPARG interaction were analyzed by Western blot and co-immunoprecipitation (Co-IP). SIRT3 and PPARG were identified as core targets of HKL, exhibiting strong binding with calculated energies of −6.834 and −6.579 kcal/mol, respectively. In MIHA cells, HGHF (40 mM Glu + 0.2–0.3 mM PA) induced lipid accumulation, including increased lipid droplets, and elevated TG (2.5–3.2-fold) and TC (2.2–2.8-fold) contents in a dose-dependent manner, accompanied by downregulated SIRT3/PPARG expression and heightened global protein acetylation. The non-cytotoxic HGHF-M condition (40 mM Glu + 0.2 mM PA) was selected for further experiments. HKL (5–10 μM) dose-dependently reduced lipid accumulation by ~38–60%, decreased TG and TC levels by up to ~13% and ~30%, and restored SIRT3/PPARG expression. The protective effects of HKL were reversed by inhibition of SIRT3 with 3-TYP. Co-IP confirmed the interaction between SIRT3 and PPARG, and SIRT3 overexpression significantly decreased the acetylation level of PPARG. This study suggests that HKL ameliorates hepatic lipid accumulation via SIRT3-mediated deacetylation of PPARG, providing an experimental basis for considering HKL as a potential therapeutic agent against metabolic disorders. Full article

Background/Objectives: Antimicrobial resistance and bacterial persistence underscore the need to develop new chemotypes with multifunctional antibacterial mechanisms. This study aimed to design, synthesize, and evaluate curcumin-inspired 3,5-diarylidene-4-piperidones as versatile small molecules exhibiting antibacterial, antibiofilm, anti-efflux, DNA gyrase-inhibitory, and antiproliferative properties. Methods: A targeted series of triazole-conjugated 3,5-diarylidene-4-piperidones was synthesized through copper-catalyzed azide-alkyne cycloaddition click chemistry and subsequently characterized using standard spectroscopic techniques. The compounds were assessed for antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. Selected active compounds underwent further evaluation for DNA gyrase inhibition, antibiofilm activity against multidrug-resistant S. aureus ATCC 33591, ethidium bromide accumulation, and antiproliferative effects on HCT116 and MCF7 cancer cells, with RPE1 cells serving as a control to evaluate cytotoxicity in normal cells. Additionally, computational studies, including QSAR analysis and molecular docking, were conducted to bolster structure–activity relationships and provide mechanistic insights. Results: Several derivatives demonstrated selective antibacterial activity against Gram-positive bacteria, particularly S. aureus, while exhibiting limited or no efficacy against E. coli. Compounds 7n and 7l emerged as the most potent against S. aureus, with minimum inhibitory concentrations (MICs) of 7.8 and 8.2 μM, respectively. Notably, compound 7l inhibited S. aureus DNA gyrase supercoiling, displaying an IC₅₀ of 3.20 μM, comparable to ciprofloxacin. Compound 7e exhibited the strongest antibiofilm activity against multidrug-resistant S. aureus, whereas compound 7a resulted in the highest accumulation of ethidium bromide, indicating robust anti-efflux activity. Antiproliferative assays revealed that select halogenated derivatives were effective against HCT116 and MCF7 cells, while the most promising antibacterial compounds exhibited minimal cytotoxicity toward RPE1 cells. Quantitative structure–activity relationship (QSAR) and docking studies supported the observed structure–activity relationships and suggested potential interactions with the ATPase binding site of DNA gyrase B. Conclusions: Triazole-conjugated 3,5-diarylidene-4-piperidones are promising multifunctional scaffolds with selective anti-S. aureus activity, antibiofilm and anti-efflux properties, and, for compound 7l, potent DNA gyrase inhibition. These findings support further optimization of this chemotype as a platform for developing antibacterial agents with polymechanistic activity. Full article

Energetic materials face dual challenges of enhancing detonation performance and replacing toxic lead-based formulations. Triazole-based energetic potassium salts typically struggle to achieve simultaneous high-density and excellent detonation properties. Herein, a novel gem-dinitro-functionalized 1,2,3-triazole energetic salt, tripotassium 4,5-bis(gem-dinitromethyl)-2H-1,2,3-triazolate (3K₃BNOT·4H₂O), was rationally designed and synthesized via a six-step mild route using diaminomaleonitrile as the starting material. The structure was fully characterized by IR, NMR, elemental analysis, and single-crystal X-ray diffraction (SC-XRD). 3K₃BNOT·4H₂O crystallizes in the triclinic system (space group P-1) and forms a three-dimensional K-O/K-N ionic coordination network, delivering an ultra-high anhydrous crystal density of 2.077 g·cm⁻³ at 193K. It exhibits a peak decomposition temperature of 183.8 °C (10 °C·min⁻¹), impact sensitivity of 5 J, and friction sensitivity of 60 N (standard BAM methods). The calculated detonation velocity and pressure reach 8836 m·s⁻¹ and 28.6 GPa, respectively, outperforming the classical explosive RDX. This work provides a structural analysis of triazole-based energetic potassium salt hydrates, and 3K₃BNOT·4H₂O shows structural potential as a high-energy energetic material; its initiating performance needs further experimental verification. Full article

We report a highly chemoselective N-sulfonylation of 3-(methylthio)-1H-1,2,4-triazol-5-amine with 4-nitrobenzenesulfonyl chloride promoted by N,N-diisopropylethylamine in acetonitrile under mild conditions. This transformation selectively affords N-(4-nitrophenyl)sulfonylation at the N1 position of the 1,2,4-triazole ring over the exocyclic amine functionality. The product was fully characterized by IR, 1D and 2D NMR spectroscopy, as well as high-resolution mass spectrometry, unequivocally confirming its molecular structure. Full article

A series of 1,2,3-triazole-linked-thiazolidine-2,4-dione hybrids (SDP1–SDP15) were designed, synthesized, and evaluated for their antidiabetic potential. All structures were characterized by FT-IR and NMR spectroscopy (¹H and ¹³C). All derivatives exhibited significant in vitro inhibition of α-glucosidase (IC₅₀: 24.17–46.41 µg/mL) and α-amylase (23.25–50.66 µg/mL), comparable to the standard drug acarbose (IC₅₀: 25.18 and 32.53 µg/mL) and superior to the reference drug pioglitazone (IC₅₀: 84.24 and 79.74 µg/mL) for α-glucosidase and α-amylase, respectively. Molecule SDP8 emerged as the most potent with an IC50 of 24.17 and 23.25 µg/mL for α-glucosidase and α-amylase, respectively. Further, SDP8 exhibited a higher docking score of −10.7 kcal/mol and −10.4 kcal/mol against α-glucosidase and α-amylase than pioglitazone (−8.1 kcal/mol and −7.7 kcal/mol, respectively), suggesting that interaction with these two enzymes may be the cause for its antidiabetic activity. Furthermore, DFT analysis revealed favorable electronic properties with a low HOMO-LUMO energy gap, whereas ADMET predictions revealed moderate drug-like characteristics with some limitations, such as poor solubility, relatively high lipophilicity, and partial noncompliance with drug-likeness regulations. Overall, these results highlight triazole-linked thiazolidinedione hybrids as promising candidates for further development in T2DM, with SDP8 serving as a preliminary lead requiring additional optimization and validation. Full article

In this report, we describe the synthesis of two new celastrol derivatives featuring aryl-substituted 1,2,3-triazole fragments attached to the celastrol scaffold via an ester linkage. The target compounds, incorporating 4-methoxyphenyl and p-tert-butylphenyl groups, were characterized by ¹H and ¹³C NMR spectroscopy, FTIR, UV-Vis, HRMS, melting point determination, and specific rotation measurements. Full article

Candida albicans remains one of the leading causes of invasive fungal infections and is recognized as a critical-priority pathogen by the World Health Organization. The increasing emergence of resistance to azole antifungals such as fluconazole highlights the need for alternative therapeutic strategies. In this study, we evaluated the antifungal potential of a chromium(III)–triazole coordination complex (CrL1) against C. albicans. In vitro susceptibility testing showed that CrL1 exhibited notable antifungal activity against the fluconazole-resistant strain with low cytotoxicity in murine macrophages. To facilitate aqueous dispersion and enable in vivo administration, CrL1 was incorporated into an oil-in-water nanoemulsion (NE-CrL1). The antifungal activity of NE-CrL1 was evaluated in a murine model of invasive candidiasis. In mice infected with a fluconazole-resistant C. albicans strain, treatment with NE-CrL1 reduced renal fungal burden and was associated with attenuation of histopathological alterations and changes in local inflammatory responses. Although the present study has limitations, including the absence of mechanistic assays and additional physicochemical characterization, these results suggest in vivo antifungal activity of NE-CrL1 and warrant further preclinical evaluation against drug-resistant Candida infections. Full article

A hybrid method combining biomimetic liquid chromatography with immobilized artificial membrane (IAM) and quantitative structure–activity relationships (QSARs) was used to derive helpful models for predicting selected properties related to distribution (binding to human serum albumin (log P_w/HSA)) and absorption (skin permeation (log K_w/sp), plant cuticle permeation (log P_w/pc), and human intestinal permeability (Caco-2)), and therefore influencing the effectiveness or unwanted effects of 199 synthetic compounds that are regarded as potential drugs or plant protection products. The molecules under investigation—derivatives of 5H-6,7-dihydroimidazo [2,1-c][1,2,4]triazole, 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one, 2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione, 1H-1,2,4-triazole, carbamic and phenoxyacetic acid—differ in their properties but all meet the requirements for xenobiotics to be considered as medicinal products. Reliable high-concept models were developed, indicating lipophilicity, molecular size, electronic properties, and the number of rotatable bonds as descriptors that determine the biological properties of these compounds. These models have been optimized and cross-validated, confirming their reliability and high predictivity. Full article

Objective: Posaconazole, a second-generation triazole antifungal used for the prevention or treatment of invasive fungal infections, has been shown to markedly increase tacrolimus exposure in vivo when co-administered, potentially leading to clinically significant adverse events. A physiologically based pharmacokinetic (PBPK) model was developed to predict tacrolimus–posaconazole interactions in renal transplant recipients with different CYP3A5 genotypes, to inform tacrolimus dose adjustment in clinical practice. Methods: First, to obtain the critical inhibition parameters, in vitro enzyme kinetic studies were conducted. Based on these data, a whole-body physiologically based pharmacokinetic (PBPK) model for TAC was developed and validated in PK-Sim. A published, validated posaconazole PBPK model was applied concurrently. Model performance was evaluated against published pharmacokinetic data in healthy volunteers receiving tacrolimus with posaconazole. A virtual Chinese renal transplant recipient was generated by incorporating population-specific physiological parameters, including CYP3A5 genotype-dependent enzyme expression. Results: In vitro experimental results demonstrated that POSA acts as a potent reversible competitive inhibitor of CYP3A4/5-mediated TAC metabolism. The tacrolimus PBPK model adequately captured pharmacokinetics across CYP3A5 genotypes, and tacrolimus pharmacokinetics during co-administration with posaconazole were also predicted. Compared with CYP3A5 expressers, nonexpressers showed greater variability in tacrolimus whole-blood concentrations and greater susceptibility to posaconazole-mediated interactions. The CYP3A5*3*3 genotype was associated with higher C_max and AUC. Dose optimization simulations predicted that after 6–7 days of posaconazole co-administration, nonexpressers would require the reduction of tacrolimus dosing frequency from every 12 h to every 24 h to maintain trough concentrations within 8–15 ng/mL, whereas a 50% dose reduction was predicted to be optimal for expressers. Conclusions: A tacrolimus–posaconazole PBPK drug–drug interaction model was developed for the population of renal transplant recipients and used to simulate tacrolimus trough concentrations across CYP3A5 genotypes and dosing regimens, supporting genotype-informed co-administration in clinical practice. Full article

Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold. Full article

Paclobutrazol (PBZ) is a triazole-type plant growth regulator that interferes with gibberellin (GAs) biosynthesis by blocking the oxidation step that converts ent-kaurene into ent-kaurenoic acid; however, the developmental mechanisms linking GAs restriction with storage organ enlargement remain poorly understood. In potato, PBZ induces compact growth while promoting microtubers (MTs) expansion, suggesting that GAs depletion triggers coordinated developmental reprogramming rather than simply suppressing elongation. Here, we evaluated the phenotypic, histological, and transcriptomic responses associated with PBZ-induced MTs development in Solanum tuberosum L. PBZ treatment, which increased MTs size, suppressed stolon growth, and enhanced starch accumulation, indicating a shift toward storage tissue development. Transcriptomic analysis identified broad PBZ-responsive changes, including enrichment of pathways related to metabolism, ribosome function, carbon metabolism, plant hormone signaling, and cell cycle regulation. Network analyses revealed ATH1-associated modules connected with receptor-like kinases, transcriptional regulators, mitotic regulators, replication-licensing factors and condensin components, supporting coordinated regulation among growth control, localized proliferation, asymmetric division, endoreduplication, and chromatin stability. These patterns were further supported by the absence of a detectable gibberellic acid (GA₃) peak in PBZ-treated samples. These findings support a model in which PBZ-responsive signaling is associated with developmental reprogramming toward radial expansion and reinforcement of storage tissue, providing a regulatory mechanism by which growth repression is coupled to microtube enlargement in potato. Full article

4-Sulfanyl-1,2,3-triazole (L1) accelerated the solvent-free CuAAC efficiently with low catalyst loading (0.1 mol% for common azides and 1 mol% for sulfonyl azides). L1 exhibited higher catalytic activity compared to 1,4-substituted 1,2,3-triazole without sulfanyl group (5a) and sulfide, demonstrating that coordination of both sulfanyl and 1,2,3-triazole moieties with copper was critical to enhance the activity of L1. The Cu(OAc)₂/L1 catalytic system displayed high selectivity in synthesis of alkynyl- or azido-involved 1,2,3-triazoles. The di-copper system Cu(OAc)₂/CuBr/L1 promoted the reaction of electron-deficient and less reactive sulfonyl azides well, generating N-sulfonyl-1,2,3-triazoles in good yields, and L1 showed better performance than 1,3-di-o-tolylthiourea (L′). Other features of this protocol included recyclable ligand, 1:1 substance ratio, high yields, wide substance scope, and easily scaled up and facile purification of most products. Full article

Interpretation of pharmacometabolomics results, aiming particularly at biomarker (sets) discovery for drug exposure, remains a major challenge. The metabotyping of drug exposure depends on resolution of specific metabolomics techniques and comprises individual metabolic phenotypes (“metabotypes”), disease-, drug- and microbiome-specific patterns, as well as conditional metabolic states (e. g. fasting). In this clinical trial with 16 healthy participants, an exploratory objective was to evaluate the untargeted urinary metabolomics of voriconazole, administered in four single doses, using proton nuclear magnetic resonance (¹H-NMR) spectroscopy. Voriconazole is a second-generation triazole and a potent inhibitor of drug-metabolizing enzymes such as cytochrome P450 (CYP) isozymes CYP3A4 and CYP2C19. Therefore, identification of metabolites reflecting acute CYP3A4 inhibition was of particular interest. On two treatment days without and with voriconazole (with background microdosed midazolam and omeprazole administration for CYP3A4 and CYP2C19 phenotyping, respectively), spot urine was collected after overnight fasting (predose) and 4 h later (postdose fasting). In the postdose versus predose fingerprints, most changes at the annotated metabolite level were attributable to fasting metabolomics or potential confounders. ¹H-NMR spectroscopy identified neither a short-term voriconazole-specific signature nor patterns or metabolites potentially reflecting acute CYP3A4 inhibition. Our study emphasizes crucial significance of strict standardization of fasting time and minimization of confounder influences by clinical trial design as well as selection of adequate baselines and high-resolution analytical techniques in pharmacometabolomics research, especially for biomarker discovery. Full article