Kumar Pardeep, Malik Pradip, Ali Juned, Saxena Deepanshi, Singampalli Anuradha, Rani Bandela, Bellapukonda Sri Mounika, Devi Ankita, Bhale Nagesh A, Dikundwar Amol G, Nanduri Srinivas, Dasgupta Arunava, Chopra Sidharth, Madhavi Yaddanapudi Venkata
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Janakipuram Extension, Lucknow, Uttar Pradesh, India.
Arch Pharm (Weinheim). 2025 Aug;358(8):e70074. doi: 10.1002/ardp.70074.
The escalating threat of drug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery of novel chemotherapeutic agents. In this study, a series of dihydroindazole-based derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. Among the synthesized compounds, 8u exhibited the most potent in vitro activity against Mtb HRv with a minimum inhibitory concentration (MIC) of 2 µg/mL, while 8i and 8q showed moderate activity (MIC = 8 µg/mL). Several analogs demonstrated MICs in the range of 16-32 µg/mL. 8u also displayed enhanced activity against single-drug-resistant Mtb strains, outperforming ethambutol and rifampicin. Structure-activity relationship analysis indicated that both the hydrazide linker and heteroaryl substitutions significantly influenced antimycobacterial activity. 8u was non-cytotoxic to Vero cells (CC₅₀ > 100 µg/mL), yielding a selectivity index (SI) > 50. Time-kill kinetics confirmed its bactericidal nature. Mechanistic investigations using molecular docking and 100-ns molecular dynamics simulations identified InhA as the probable molecular target. In silico ADMET predictions (QikProp and ProTox-3.0) supported favorable pharmacokinetic and toxicity profiles. Collectively, these findings highlight 8u as a promising lead for the development of next-generation anti-TB agents.
耐药结核分枝杆菌（Mtb）构成的威胁不断升级，因此有必要发现新型化疗药物。在本研究中，设计、合成了一系列基于二氢吲唑的衍生物，并对其抗分枝杆菌潜力进行了评估。在合成的化合物中，8u对结核分枝杆菌H37Rv表现出最强的体外活性，最低抑菌浓度（MIC）为2μg/mL，而8i和8q表现出中等活性（MIC = 8μg/mL）。几种类似物的MIC在16 - 32μg/mL范围内。8u对单耐药结核分枝杆菌菌株也表现出增强的活性，优于乙胺丁醇和利福平。构效关系分析表明，酰肼连接基和杂芳基取代均对抗分枝杆菌活性有显著影响。8u对Vero细胞无细胞毒性（CC₅₀＞100μg/mL），选择性指数（SI）＞50。时间杀菌动力学证实了其杀菌性质。使用分子对接和100 ns分子动力学模拟进行的机制研究确定InhA为可能的分子靶点。计算机辅助ADMET预测（QikProp和ProTox-3.0）支持其良好的药代动力学和毒性特征。总体而言，这些发现突出了8u作为开发下一代抗结核药物的有前景的先导化合物。
