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Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

ABSTRACT: Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 μg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 μg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

SUBMITTER: Xia MY

PROVIDER: S-EPMC10312031 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Xia Meng-Yu MY Cai Yu-Xiang YX Chen Jun-Xian JX Zhao Xin X Dong Hong-Mei HM Yang Zai-Chang ZC

Journal of enzyme inhibition and medicinal chemistry 20231201 1

Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 μg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 μg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to anima ...[more]

PMID: 37381729

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Project description:Currently, available therapies for diabetes cannot achieve normal sugar values in a high percentage of treated patients. This work synthesized a series of carbazole-triazole-thione derivatives, and their potential antidiabetic activity was investigated against the key diabetic enzymes α-amylase and glycosidase. Normal human hepatic stellate cells (LX-2) were employed to assess their cytotoxicity and safety, followed by in vivo testing to investigate the hypoglycemic effect of the most promising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione derivatives were synthesized. Seven structures demonstrated potential inhibitory activity against α-amylase enzyme, with IC50 lower than 6.4 μM. Among them, compounds C5f, C5o, and C5r exhibited the highest potency, with IC50 values of 0.56, 0.53, and 0.97 μM, respectively, compared to the well-known α-amylase inhibitor acarbose, which has an IC50 value of 5.31 μM. Exploring the inhibition potency of these series against α-glucosidase enzyme revealed that C5f and C5r compounds act as moderate inhibitors, with IC50 values of 11.03 and 13.76 μM, respectively. Moreover, at 100 μM concentration, most of the evaluated compounds showed negligible cytotoxic effect against LX-2 cell lines, particularly compounds C5o and C5s, that demonstrated lower cytotoxic activity by 3-fold compared to the positive control 5-Flururicle (cell viability 13.45%). Thus, the C5f compound was selected for in vivo evaluation, and after administering five doses of this compound (10 mg/kg) to group III of mice, a significant reduction in glucose concentration was observed, bringing it down from 290.54 to 216.15 mg/dL, in comparison with the control group which did not show a reduction in blood glucose level. These observed in vitro and in vivo results were upheld by performing a set of chemoinformatic studies that elucidated the binding interactions of the most active derivatives within the enzyme's active site and highlighted the critical roles of both the 1,2,4-triazole-3-thione and carbazole scaffolds in these interactions. Finally, the drug-likeness profiles of our carbazole-triazole-thione derivatives suggest their potential as candidates for further in vivo studies and clinical trials.

Dataset Information

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Publications

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

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