Exploration of New Dihydroindazole Derivatives as Promising Anti-TB Agents: Design, Synthesis, In Silico, and Biological Evaluation

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Pardeep Kumar, Pradip Malik, Juned Ali, Deepanshi Saxena, Anuradha Singampalli, Bandela Rani, Sri Mounika Bellapukonda, Ankita Devi, Nagesh A. Bhale, Amol G. Dikundwar, Srinivas Nanduri, Arunava Dasgupta, Sidharth Chopra, Yaddanapudi Venkata Madhavi
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Abstract

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 H37Rv 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.

Abstract Image

新型抗结核药物双氢茚唑衍生物的探索:设计、合成、硅合成和生物学评价
耐药结核分枝杆菌(Mtb)的威胁不断升级,需要发现新的化疗药物。本研究设计、合成了一系列以二氢茚唑为基础的衍生物,并对其抑菌潜力进行了评价。在所合成的化合物中,8u对Mtb H37Rv的体外活性最强,最低抑制浓度(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范围为16-32µg/mL。8u还显示出对单药耐药结核分枝杆菌菌株的增强活性,优于乙胺丁醇和利福平。构效关系分析表明,酰肼连接剂和杂芳基取代对抗菌活性均有显著影响。8u对Vero细胞无细胞毒性(CC₅0 > 100 μ g/mL),产生选择性指数(SI) > 50。时间杀伤动力学证实了其杀菌性质。通过分子对接和100-ns分子动力学模拟,机制研究确定InhA为可能的分子靶标。计算机ADMET预测(QikProp和ProTox-3.0)支持有利的药代动力学和毒性谱。总的来说,这些发现突出了8u是开发下一代抗结核药物的有希望的先导。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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