Search Results (772)

Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article

Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis of 15 differently substituted 2H-1,2,3-triazole-based hydroxamide analogs by employing triazole ring as a cap with varied linker fragments. The compounds were evaluated for their anticancer effect, especially their anti-breast cancer response. Molecular docking and molecular dynamics simulations were conducted to examine binding interactions. Results: Results indicated that among all synthesized hybrids, the molecule VI(i) inhibits the growth of MCF-7 and A-549 cells (GI₅₀ < 10 μg/mL) in an antiproliferative assay. Compound VI(i) was also tested for cytotoxic activity by employing an MTT assay against A549, MCF-7, and MDA-MB-231 cell lines, and the findings indicate its potent anticancer response, especially against MCF-7 cells with IC₅₀ of 60 µg/mL. However, it experiences minimal toxicity towards the normal cell line (HEK-293). Mechanistic studies revealed a dual-pathway activation: first, apoptosis (17.18% of early and 10.22% of late apoptotic cells by annexin V/PI analysis); second, cell cycle arrest at the S and G2/M phases. It also promotes ROS generation in a concentration-dependent manner. The HDAC–inhibitory assay, extended in silico molecular docking, and MD simulation experiments further validated its significant binding affinity towards HDAC 1 and 6 isoforms. DFT and ADMET screening further support the biological proclivity of the title compounds. The notable biological contribution of VI(i) highlights it as a potential candidate, especially against breast cancer cells. Full article

In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds 4b and 4g (IC₅₀ = 4.5 μM) are the most potent within the series followed by compound 6a (IC₅₀ = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound 4g exhibited a docking score of −9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π−cation interaction with Lys526. Full article

This study focuses on the search for new effective synthetic antimicrobial compounds as a tool against the widespread presence of microorganisms resistant to existing drugs. Five derivatives of [1,3]thiazolo[3,2-b][1,2,4]triazoles were synthesized using an accessible protocol based on electrophilic heterocyclization and were characterized using infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies, and their in vitro antimicrobial and antifungal activities were evaluated using the agar plate diffusion method and the microdilution plate procedure. Both antibacterial (Gram-positive and Gram-negative) and antifungal activities were found for the examined samples. The minimum inhibitory concentration (MIC) varied from 0.97 to 250 µg/mL, and the minimum bactericidal concentration (MBC) from 1.95 to 500 µg/mL. Compound 2a showed good antifungal action against Candida albicans and Saccharomyces cerevisiae with minimum fungicidal concentration (MFC) 125 and MIC 31.25 µg/mL. The molecular docking revealed that the 2-heptyl-3-phenyl-6,6-trimethyl-5,6-dihydro-3H-[1,3]thiazolo[3,2-b][1,2,4]triazol-7-ium cation stands out as a highly promising candidate for further investigation due to a wide range of interactions, including conventional hydrogen bonds, π–σ, π–π T-shaped, and hydrophobic alkyl interactions. The synthesis and preliminary evaluation of [1,3]thiazolo[3,2-b][1,2,4]triazoles yielded promising antimicrobial and antifungal candidates. The diverse interaction profile of the 2-heptyl derivative salt allows this compound’s selection for further biological studies. Full article

Cancer remains one of the leading causes of death globally, highlighting the urgent need for novel anticancer therapies with higher efficacy and reduced toxicity. Similarly, the rise in multidrug-resistant pathogens and emerging infectious diseases underscores the critical demand for new antimicrobial agents that target resistant infections through unique mechanisms. This study used computational approaches to investigate twenty quinolone–triazole and conazole–triazole hybrid derivatives as antimicrobial and anticancer agents (1–20) with nine reference drugs. By studying their interactions with 6 bacterial DNA gyrase and 10 cancer-inducing target proteins (E. faecalis, M. tuberculosis, S. aureus, E. coli, M. smegmatis, P. aeruginosa and EGFR, MPO, VEGFR, CDK6, MMP1, Bcl-2, LSD1, HDAC6, Aromatase, ALOX15) and comparing them with established drugs such as ampicillin, cefatrizine, fluconazole, gemcitabine, itraconazole, ribavirin, rufinamide, streptomycin, and tazobactam, compounds 15 and 16 emerged as noteworthy antimicrobial and anticancer agents, respectively. In molecular dynamics simulations, compounds 15 and 16 had the strongest binding at −10.6 kcal mol⁻¹ and −12.0 kcal mol⁻¹ with the crucial 5CDQ and 2Z3Y proteins, respectively, exceeded drug-likeness criteria, and displayed extraordinary stability within the enzyme’s pocket over varied temperatures (300–320 K). In addition, we used density functional theory (DFT) to calculate dipole moments and molecular orbital characteristics and analyze the thermodynamic stability of putative antimicrobial and anticancer derivatives. This finding reveals a well-defined, possibly therapeutic relationship, supported by theoretical and future in vitro and in vivo studies. Compounds 15 and 16, thus, emerged as intriguing contenders in the fight against infectious diseases and cancer. Full article

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential. Full article

A series of novel N-Mannich bases derived from a dimethylpyridine–1,2,4-triazole hybrid was synthesized and evaluated in vitro for cytotoxic activity on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, and HT-29). Compound 6 bearing a phenyl group at the N-4 position and a 4-methylphenyl piperazine moiety at the N-2 position of the 1,2,4-triazole-3-thione scaffold exerted good cytotoxic activities on EPG and Caco-2 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal colonic epithelial cells (CCD 841 CoTr). Further evaluation revealed the good ability of compound 6 to inhibit the efflux function of P-glycoprotein in P-gp-expressing cell lines (HT-29, LoVo, and LoVo/Dx). Moreover, compound 6 induced apoptotic cell death through a significant increase in the caspase-3 and p53 protein levels in HT-29 cells. Finally, the molecular docking method was applied to explain our experimental findings. The molecular modeling study based on Density Functional Theory (DFT) and the Quantum Theory of Atoms in Molecules (QTAIM) analysis provided insight into the geometric and electronic structure properties of the compounds. Full article

To further extend the structure–activity relationships on previously identified anti-proliferative imidazo-pyrazoles, a novel series of compounds was designed and synthesized. In the obtained derivatives (1), the imidazo-pyrazole scaffold was formally condensed with a substituted triazole moiety, known for its biological properties. All derivatives were tested for anti-proliferative activity on a panel of 60 different cancer cell lines and compound 1h was identified as the most promising derivative, being highly effective against melanoma cells. Additional investigations demonstrated a cytotoxic and pro-oxidant action of the compound 1h on human metastatic melanoma cell lines (MeOV and MeTA) but not on healthy keratinocytes (HaCAT), confirming the selective activity of the compound. In silico calculations predicted favorable drug-like and pharmacokinetic properties and pre-formulation studies evaluated the effect of Tween 80 on 1h solubility. Overall, the collected data confirmed the pharmacological potential of the imidazo-pyrazole scaffold and indicated 1h as an interesting lead structure for the development of novel anti-melanoma agents. Full article

In this study, a C-C bond-linked triazole-fused oxadiazole energetic compound, 4-amino-5-(4-amino-1,2,5-oxadiazol-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1), was successfully designed and efficiently synthesized. Following nitration, a functional group-modified nitramine energetic compound (2) was obtained, and its energetic ionic salt (3) was further prepared. A comprehensive characterization of the structures of these three compounds was conducted, resulting in the successful elucidation of the single-crystal structures of compound 2·Ca²⁺·6H₂O and compound 3·MeOH. Compound 2 exhibited a positive formation enthalpy (56.2 kJ·mol⁻¹) and moderate mechanical sensitivity (FS = 120 N, IS = 12 J). Due to the presence of the nitramine group, compound 2 exhibited a relatively low thermal decomposition temperature (T_dec = 94 °C). However, the thermal stability of compound 3 was significantly improved (T_dec = 233 °C), which is attributed to salt formation. Compound 3 exhibits a positive formation enthalpy (121.0 kJ·mol⁻¹), along with excellent detonation performance (D = 8120 m·s⁻¹, P = 32.1 GPa) and reduced mechanical sensitivity (FS = 224 N, IS = 24 J). Therefore, the multi-heterocyclic compound, joined via C-C bond linkage, demonstrates outstanding performance, offering a new avenue for the design and synthesis of energetic materials. Full article

Due to their rare properties of solid-state luminescence enhancement (SLE), tricarbonylrhenium complexes are promising candidates for applications as photoluminescent materials. However, the effect of isomerism on optical properties is still not well known. The aim of this in-depth study is to explore the behavior of a 2-(1,2,3-triazol-1-yl)pyridine (tapy) complex and compare it with that of the isomers studied previously. Two derivatives that incorporate a mesoionic carbene ligand and represent an emerging class of molecules were also synthesized and compared with the corresponding isomers. The crystallographic data revealed that compounds in the solid state have little or no π–π interactions. The spectroscopic study was supported by DFT calculations. All the compounds were weakly phosphorescent in solution but exhibited a marked SLE effect. The Re-Tapy complex is an excellent solid-state emitter (PLQY = 0.62), well suited for applications related to aggregation-induced phosphorescence emission (AIPE). Its sensitivity to mechanical stimuli was unprecedented among the isomers considered to date. On the other hand, triazolylidene complexes are less emissive than their pyta_(1,2,3) counterparts. This study shows how the ligand isomerism influences the optical properties of tricarbonylrhenium(I) complexes. It indicates that selecting the right pattern is a key factor for the design of efficient photoluminescent materials. Full article

Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N⁵,N³-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC₅₀ to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors. Full article

We report on the synthesis and characterization of a novel fluorenyl-methoxycarbonyl (Fmoc)-containing thioxo-triazole-bearing dipeptide 5, evaluated for potential therapeutic applications. The compound was tested for its antioxidant and antimicrobial properties, demonstrating significant effects in scavenging reactive oxygen species (ROS) and inhibiting microbial growth, particularly when combined with plant extracts from an endemic Peonia species from the Caucasus. Circular dichroism (CD) binding studies with bovine serum albumin (BSA) and calf thymus DNA revealed important interactions, suggesting the dipeptide’s potential in biomedically relevant conditions that involve DNA modulation. Molecular docking and CD spectra deconvolution provided additional insights into the binding mechanisms and structural characteristics of the formed complexes with the biomolecular targets. The Fmoc group enhances the dipeptide’s lipophilicity, which may facilitate its interaction with cellular membranes, supporting efficient drug delivery. A computational evaluation at the ωB97XD/aug-cc-pVDZ level of theory was carried out, confirming the experimental results and revealing a powerful potential of the peptide as an antioxidant, through FMOs, MEP analysis, and antioxidant mechanism assessments. Together, these findings suggest that this dipeptide could be valuable as an antimicrobial and antioxidant agent, with potential applications in pathologies involving oxidative stress, DNA modulation, and microbial infections. Full article

Energetic complexes with multi-component architectures represent a frontier in contemporary energetic materials research. In this work, we report a novel high-energy complex—bis(5-nitro-3-(dinitromethyl)-1,2,4-triazole)-hexaamminecobalt(III) [[Co(NH₃)₆](HNTD)(NTD)·H₂O]—that is synthesized using the oxygen-rich energetic compound 5-nitro-3-(trinitromethyl)-1,2,4-triazole (HNTF) as a precursor. Compared with metallic H₂NTD salts, [Co(NH₃)₆](HNTD)(NTD)·H₂O exhibits a higher density (ρ = 1.886 g cm⁻³) and unrivaled energy properties (V_d = 8030 m s⁻¹ and P = 29.2 GPa). The formation of a dense hydrogen-bonding network—mediated by ammonium groups in the [Co(NH₃)₆]³⁺ core and nitro groups of HNTD⁻ and NTD²⁻—significantly dampens the mechanical sensitivity (IS = 10 J and FS = 140 N). These combined attributes establish [Co(NH₃)₆](HNTD)(NTD)·H₂O as a promising high-energy-density material (HEDM), offering critical insights for the design of next-generation energetic complexes. Full article

The substituent effects on crystal stacking topology and stability of the 5,5-dinitro-2H,2H-3,3-bi-1,2,4-triazole (DNBT) and its three energetic cocrystals with 1,3,5-trinitrobenzene (TNB), 2,4,6-trinitrotoluene (TNT), and picric acid (PA) were systematically investigated through combined density functional theory (DFT) calculations and classical molecular dynamics (MD) simulations. The interaction mechanism and detonation performance of the three energetic cocrystals were implemented to the electrostatic potential (ESP), Hirshfeld surface analysis, radial distribution function (RDF), binding energy, and detonation parameters. In contrast to N-H⋯O interactions in DNBT, three cocrystals exhibited more distinctly weak C-H⋯O intermolecular hydrogen bonds and NO₂-π stacking interactions to stabilize the lattice. Notably, the highest binding energy of PA/DNBT shows the largest stability and lowest impact sensitivity is related to the more intermolecular interactions. Although the introduction of substituents slightly affects the crystal density of DNBT crystals, it significantly reduces the impact sensitivity. Moreover, the balanced detonation performance and impact sensitivity of DNBT-based cocrystals make it a candidate to expand the applications of DNBT crystals. These findings contribute to a broadened understanding of construction and design strategies for the energy release mechanisms of energetic compounds with the azoles ring family. Full article

A series of novel hybrid uracil derivatives incorporating the natural alkaloids caffeine or gramine, linked via 1,2,3-triazole ring, were synthetized using click chemistry. The structures of the obtained compounds were confirmed by spectroscopic methods, including ¹H NMR, ¹³C NMR, FT-IR, and mass spectrometry. The biological activity of hybrids was evaluated in vitro, including assessments of hemolytic activity, antioxidant potential, antifungal efficacy, and antibacterial activity. Additionally, molecular docking studies were conducted in silico for the most active antioxidant candidate. The results revealed that the hemocompatibility of the derivatives was structure-dependent. While caffeine-containing hybrids exhibited moderate-to-low cytoprotective activity under oxidative stress conditions, those incorporating gramine showed significantly higher potency. A plausible molecular mechanism underlying their cytoprotective activity is proposed. Several compounds also inhibited the growth of the plant pathogens Fusarium culmorum and Botrytis cinerea. The promising antioxidant and antifungal properties of selected uracil–alkaloid hybrids highlight their potential as multifunctional bioactive compounds for managing oxidative stress and controlling plant pathogens. Furthermore, the finding demonstrates the effectiveness of click chemistry as a versatile tool for the synthesis of bioactive heterocyclic compounds. Full article