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

IF 3.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2025-07-04 DOI:10.1080/17568919.2025.2525069

Pardeep Kumar, Pradip Malik, Juned Ali, Deepanshi Saxena, Anuradha Singampalli, Rani Bandela, Sri Mounika Bellapukonda, Sugali Indravath Rajyalakshmi, Nagesh A Bhale, Amol G Dikundwar, Srinivas Nanduri, Arunava Dasgupta, Sidharth Chopra, Venkata Madhavi Yaddanapudi

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Abstract

Background: Development of new effective drugs against multidrug resistant Mycobacterium tuberculosis is the need of the hour to combat tuberculosis (TB) disease.

Materials and methods: 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.

Results: All compounds displayed excellent MICs in the range of 0.125-16 µg/mL. The most potent compound, 6q, with an MIC of 0.125 µg/mL showed bactericidal effect and was effective on ethambutol and streptomycin resistant Mtb strains with an MIC of 0.03 µg/mL and rifampicin resistant Mtb strain with an MIC of 0.25 µg/mL.

Conclusion: The pyrazole clubbed with pyridine-4-carbohydrazide is a potential scaffold for further exploration as anti-TB agent.

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以吡唑为基础的吡啶-4-碳肼衍生物作为耐药结核分枝杆菌制剂的探索：设计、合成、生物学评价和计算机研究。

背景：开发新的抗多药耐药结核分枝杆菌的有效药物是对抗结核病的迫切需要。材料与方法：利用吡啶-4-碳肼和取代吡唑醛合成靶分子（6a-r），对H37Rv和耐药结核菌株进行抗药评价。进行时间杀灭动力学试验以检查杀菌/抑菌效果，分子对接，对烯酰酰基载体蛋白还原酶（InhA）进行100 ns以上的动力学模拟，并进行QSAR， ADMET谱预测。结果：所有化合物在0.125 ~ 16µg/mL范围内均表现出良好的mic。最有效的化合物6q的MIC为0.125µg/mL，对乙胺丁醇和链霉素耐药Mtb菌株（MIC为0.03µg/mL）和利福平耐药Mtb菌株（MIC为0.25µg/mL）均有效。结论：吡唑与吡啶-4-碳酰肼的棒状结构是一种有潜力的抗结核药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.