Exploration of pyrazole-based pyridine-4-carbohydrazide derivatives as drug-resistant <i>Mtb</i> agents: design, synthesis, biological evaluation, and <i>in-silico</i> studies

Development of new effective drugs against multidrug resistant <i>Mycobacterium tuberculosis</i> is the need of the hour to combat tuberculosis (TB) disease. Pyridine-4-carbohydrazide and substituted pyrazole aldehydes were used to synthesize target molecules (6a-r) which were evaluated against H₃₇Rv and drug-resistant TB strains. Time kill kinetics assay was performed to check bactericidal/bacteriostatic effect, molecular docking, dynamics simulation over 100 ns was performed against enoyl acyl carrier protein reductase (InhA) along with QSAR, ADMET profile prediction. All compounds displayed excellent MICs in the range of 0.125–16 <i>µ</i>g/mL. The most potent compound, 6q, with an MIC of 0.125 <i>µ</i>g/mL showed bactericidal effect and was effective on ethambutol and streptomycin resistant <i>Mtb</i> strains with an MIC of 0.03 <i>µ</i>g/mL and rifampicin resistant <i>Mtb</i> strain with an MIC of 0.25 <i>µ</i>g/mL. The pyrazole clubbed with pyridine-4-carbohydrazide is a potential scaffold for further exploration as anti-TB agent.

开发针对多重耐药结核分枝杆菌（*Mycobacterium tuberculosis*）的新型有效药物，是当前抗击结核病（TB）的迫切需求。本研究以吡啶-4-甲酰肼（Pyridine-4-carbohydrazide）与取代吡唑醛为原料，合成目标分子6a-r，并针对H₃₇Rv菌株及耐药结核分枝杆菌菌株开展活性评价。通过时间杀菌动力学试验检测其杀菌/抑菌活性，同时针对烯酰基载体蛋白还原酶（enoyl acyl carrier protein reductase, InhA）开展分子对接及100 ns分子动力学模拟，并完成定量构效关系（QSAR）、ADMET成药性预测。所有受试化合物的最低抑菌浓度（MIC）范围为0.125~16 μg/mL。活性最优的化合物6q，其最低抑菌浓度为0.125 μg/mL，表现出杀菌活性；其对乙胺丁醇、链霉素耐药的结核分枝杆菌（Mtb）菌株的最低抑菌浓度低至0.03 μg/mL，对利福平耐药的结核分枝杆菌菌株的最低抑菌浓度为0.25 μg/mL。吡啶-4-甲酰肼偶联的吡唑类骨架是极具潜力的抗结核药物候选骨架，可用于后续抗结核药物的开发与探索。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于新型吡唑基吡啶-4-碳酰肼衍生物作为抗耐药结核分枝杆菌（Mtb）制剂的研究。通过设计、合成和生物评价，所有化合物显示出优异的抗菌活性（MIC范围0.125–16 µg/mL），其中化合物6q对耐药菌株尤其有效。研究结合了计算机模拟（如分子对接、动力学模拟）和ADMET预测，为开发抗结核药物提供了潜在支架。