Search Results (652)

In this study, a series of novel β-phenylalanine derivatives were synthesised and evaluated for their anticancer activity. The 3-(4-methylbenzene-1-sulfonamido)-3-phenylpropanoic acid (2) was prepared using β-phenylalanine as a core scaffold. The β-amino acid derivative 2 was converted to the corresponding hydrazide 4, which enabled the development of structurally diverse heterocyclic derivatives including pyrrole 5, pyrazole 6, thiadiazole 8, oxadiazole 11, triazoles 9 and 12 with Schiff base analogues 13 and series1,2,4-triazolo [3,4-b][1,3,4]thiadiazines 14. These modifications were designed to enhance chemical stability, solubility, and biological activity. All compounds were initially screened for cytotoxicity against the A549 human lung adenocarcinoma cell line, identifying N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxo-1-phenylpropyl]-4-methylbenzenesulfonamide (5) and (E)-N-{2-[4-[(4-chlorobenzylidene)amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-phenylethyl}-4-methylbenzenesulfonamide (13b) as the most active. The two lead candidates were further evaluated in H69 and H69AR small cell lung cancer lines to assess activity in drug-sensitive and multidrug-resistant models. Schiff base 13b containing a 4-chlorophenyl moiety, retained potent antiproliferative activity in both H69 and H69AR cells, comparable to cisplatin, while compound 5 lost efficacy in the resistant phenotype. These findings suggest Schiff base derivative 13b may overcome drug resistance mechanisms, a limitation commonly encountered with standard chemotherapeutics such as doxorubicin. These results demonstrate the potential role of β-phenylalanine derivatives, azole-containing sulphonamides, as promising scaffolds for the development of novel anticancer agents, particularly in the context of lung cancer and drug-resistant tumours. Full article

Antioxidative neuroprotection is effective at preventing ischemic stroke (IS). Ferulic acid (FA) offers benefits in the treatment of many diseases, mostly due to its antioxidant activities. In this study, a glycosylated ferulic acid conjugate (FA-Glu), with 1,2,3-triazole as a linker and bioisostere between glucose at the C6 position and FA at the C4 position, was designed and synthesized. The hydrophilicity and chemical stability of FA-Glu were tested. FA-Glu’s protection against DNA oxidative cleavage was tested using pBR322 plasmid DNA under the Fenton reaction. The cytotoxicity of FA-Glu was examined via the PC12 cell and bEnd.3 cell tests. Antioxidative neuroprotection was evaluated, in vitro, via a H₂O₂-induced PC12 cell test, measuring cell viability and ROS levels. Antioxidative alleviation of cerebral ischemia–reperfusion injury (CIRI), in vivo, was evaluated using a rat middle cerebral artery occlusion (MCAO) model. The results indicated that FA-Glu was water-soluble (LogP −1.16 ± 0.01) and chemically stable. FA-Glu prevented pBR322 plasmid DNA cleavage induced via •OH radicals (SC% 88.00%). It was a non-toxic agent based on PC12 cell and bEnd.3 cell tests results. FA-Glu significantly protected against H₂O₂-induced oxidative damage in the PC12 cell (cell viability 88.12%, 100 μM) and inhibited excessive cell ROS generation (45.67% at 100 μM). FA-Glu significantly reduced the infarcted brain areas measured using TTC stain observation, quantification (FA-Glu 21.79%, FA 28.49%, I/R model 43.42%), and H&E stain histological observation. It sharply reduced the MDA level (3.26 nmol/mg protein) and significantly increased the GSH level (139.6 nmol/mg protein) and SOD level (265.19 U/mg protein). With superior performance to FA, FA-Glu is a safe agent with effective antioxidative DNA and neuronal protective actions and an ability to alleviate CIRI, which should help in the prevention of IS. 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

Tebuconazole (TBZ), a triazole-class fungicide widely used in agriculture, is frequently detected in aquatic environments due to runoff and leaching, where it poses a threat to non-target aquatic organisms. This study investigates the acute toxicity of TBZ on juvenile rainbow trout (Oncorhynchus mykiss), a commercially important cold-water fish species. The 96 h LC₅₀ value was determined to be 9.05 mg/L using probit analysis. In addition to mortality, the physiological responses of fish exposed to both LC₅₀ and maximum tolerance concentration (MTC; 6 mg/L) were evaluated through haematological and histological assessments. TBZ exposure significantly suppressed key haematological parameters, particularly WBC, RBC, HGB, HCT, and LYM, indicating immunosuppression and potential hypoxia. Histological examination revealed progressive and regressive damage in gill tissues, including epithelial lifting, hyperplasia, and hypertrophy, which were more severe in the LC₅₀ group. These alterations were quantified using a semi-quantitative scoring system. Additionally, significant changes in biochemical parameters such as ALT, AST, creatinine, total protein, and glucose levels were observed, further indicating hepatic and renal dysfunctions induced by TBZ exposure. The findings demonstrate that TBZ exposure induces substantial physiological and structural impairments in rainbow trout, highlighting the importance of assessing the ecological risks of fungicide contamination in aquatic environments. The study also provides a dose–response model that can be used to estimate mortality risk in aquaculture operations exposed to TBZ. Full article

Mechanochemical and transition-metal-catalyzed reactions of alkynes, exhibiting significant advantages like short reaction time, solvent-free, high yield and good selectivity, were considered to be green and sustainable pathways to access functionalized molecules and obtained increasing attention due to the superiorities of mechanochemical processes and the reactivities of alkynes. The ball milling and CuI-catalyzed Sonogashira coupling of alkyne and aryl iodide avoided the use of common palladium catalysts. The mechanochemical Rh(III)- and Au(I)-catalyzed C–H alkynylations of indoles formed the 2-alkynylated and 3-alkynylated indoles selectively. The mechanochemical and copper-catalyzed azide-alkyne cycloaddition (CuAAC) between alkynes and azides were developed to synthesize 1,2,3-triazoles. Isoxazole could be formed through ball-milling-enabled and Ru-promoted cycloaddition of alkyne and hydroxyimidel chloride. In this review, the generation of mechanochemical and transition-metal-catalyzed reactions of alkynes was highlighted. Firstly, the superiority and application of transition-metal-catalyzed reactions of alkynes were briefly introduced. After presenting the usefulness of green chemistry and mechanochemical reactions, mechanochemical and transition-metal-catalyzed reactions of alkynes were classified and demonstrated in detail. Based on different kinds of reactions of alkynes, mechanochemical and transition-metal-catalyzed coupling, cycloaddition and alkenylation reactions were summarized and the proposed reaction mechanisms were disclosed if available. 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

This paper introduces the nitration process of obtaining the synthetic intermediate 1-(2-chloro-4-fluoro-5-nitrobenzene)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one of pyraclostrobin using raw materials fluorobenzotriazolone, fuming nitric acid, fuming sulfuric acid, and toluene. The exothermic characteristics of the nitration, quenching, extraction, and alkali washing in the nitration reaction were studied, and the thermal decomposition risk of the raw materials and the secondary decomposition risk of the products in the nitration process were evaluated. The results showed that the thermal decomposition risk of the four raw materials was level 1. The acceptable level of runaway reaction in the nitration process was evaluated to be level 2, the acceptable level of runaway reaction in the quenching was level 3, the acceptable level of runaway reaction in the extraction and the alkali washing was level 1, the process hazard level of the nitration reaction and the quenching was evaluated to be level 5, and the process hazard level of the extraction and the alkali washing was level 1. Based on the comprehensive assessment results, targeted risk mitigation and control strategies are proposed to ensure process safety. 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

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

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

The sterol demethylation inhibitors (DMIs) are among the most widely used fungicides for controlling black Sigatoka (Mycosphaerella fijiensis) and yellow Sigatoka (Mycosphaerella musicola) in banana plantations in Brazil. Black Sigatoka is considered more important due to causing yield losses of up to 100% in commercial banana crops under predisposing conditions. In contrast, yellow Sigatoka is important due to its widespread occurrence in the country. This study aimed to determine the current sensitivity levels of Mf and Mm populations to DMI fungicides belonging to the chemical group of triazoles. Populations of both species were sampled from commercial banana plantations in Registro, Vale do Ribeira, São Paulo (SP), Ilha Solteira, Northwestern SP, and Janaúba, Northern Minas Gerais, and were further characterized phenotypically. Additionally, allelic variation in the CYP51 gene was analyzed in populations of these pathogens to identify and characterize major mutations and/or mechanisms potentially associated with resistance. Sensitivity to the triazoles propiconazole and tebuconazole was determined by calculating the 50% inhibitory concentration of mycelial growth (EC₅₀) based on dose–response curves ranging from 0 to 5 µg mL⁻¹. Variation in sensitivity to fungicides was evident with all nine Mf isolates showing moderate resistance levels to both propiconazole or tebuconazole, while 11 out of 42 Mm strains tested showed low to moderate levels of resistance to these triazoles. Mutations leading to CYP51 substitutions Y136F, Y461N/H, and Y463D in Mm and Y461D, G462D, and Y463D in Mf were associated with low or moderate levels of resistance to the triazoles. Interestingly, Y461H have not been reported before in Mm or Mf populations, and this alteration was found in combination with V106D and A446S. More complex CYP51 variants and CYP51 promoter inserts associated with upregulation of the target protein were not detected and can explain the absence of highly DMI-resistant strains in Brazil. Disease management programs that minimize reliance on fungicide sprays containing triazoles will be needed to slow down the further evolution and spread of novel CYP51 variants in Mf and Mm populations in Brazil. Full article

6-Aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC₅₀ profiling showed that 27 of the 28 derivatives had lower IC₅₀ than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC₅₀ well below 1 µM. Profiling of the most promising triazole analogue (compound 27a) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but 27a also inhibits ABL, SRC, and YES kinases. Molecular docking of 27a toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations. Full article