{"title":"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","authors":"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","doi":"10.1002/ardp.70074","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>The escalating threat of drug-resistant <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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, <b>8u</b> exhibited the most potent in vitro activity against <i>Mtb</i> H<sub>37</sub>Rv with a minimum inhibitory concentration (MIC) of 2 µg/mL, while <b>8i</b> and <b>8q</b> showed moderate activity (MIC = 8 µg/mL). Several analogs demonstrated MICs in the range of 16–32 µg/mL. <b>8u</b> also displayed enhanced activity against single-drug-resistant <i>Mtb</i> strains, outperforming ethambutol and rifampicin. Structure–activity relationship analysis indicated that both the hydrazide linker and heteroaryl substitutions significantly influenced antimycobacterial activity. <b>8u</b> 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 <b>8u</b> as a promising lead for the development of next-generation anti-TB agents.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 8","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploration of New Dihydroindazole Derivatives as Promising Anti-TB Agents: Design, Synthesis, In Silico, and Biological Evaluation\",\"authors\":\"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\",\"doi\":\"10.1002/ardp.70074\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>The escalating threat of drug-resistant <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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, <b>8u</b> exhibited the most potent in vitro activity against <i>Mtb</i> H<sub>37</sub>Rv with a minimum inhibitory concentration (MIC) of 2 µg/mL, while <b>8i</b> and <b>8q</b> showed moderate activity (MIC = 8 µg/mL). Several analogs demonstrated MICs in the range of 16–32 µg/mL. <b>8u</b> also displayed enhanced activity against single-drug-resistant <i>Mtb</i> strains, outperforming ethambutol and rifampicin. Structure–activity relationship analysis indicated that both the hydrazide linker and heteroaryl substitutions significantly influenced antimycobacterial activity. <b>8u</b> 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 <b>8u</b> as a promising lead for the development of next-generation anti-TB agents.</p></div>\",\"PeriodicalId\":128,\"journal\":{\"name\":\"Archiv der Pharmazie\",\"volume\":\"358 8\",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archiv der Pharmazie\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70074\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70074","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Exploration of New Dihydroindazole Derivatives as Promising Anti-TB Agents: Design, Synthesis, In Silico, and Biological Evaluation
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.
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.