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<p>A series of 1H-indazole derivatives were synthesized using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) as a coupling agent and evaluated for their dual biological activity against <i>Mycobacterium tuberculosis</i> (Mtb) and non-small cell lung cancer (NSCLC). Molecular docking and molecular dynamics (MD) simulations identified (2,5-dimethoxyphenyl)-(5-nitro-1H-indazol-1-yl)methanone (compound <b>11</b>) was the most promising candidate, showing stable binding to the InhA enzyme with a binding energy of −9.76 kcal/mol. Compound <b>11</b> exhibited strong antitubercular activity (MIC 3.2 µg/mL), potent cytotoxicity against A549 cancer cells (78.45%), and significant anti-inflammatory effect (92.98% edema inhibition at 12h). Other derivatives also demonstrated noteworthy antimycobacterial and anti-inflammatory properties. Molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamic simulation (MDS) supported the favourable binding affinities and complex stability of the lead compound. Absorption, distribution, metabolism, and excretion (ADME) predictions confirmed drug-likeness with good gastrointestinal absorption and no violations of Lipinski's rule. The combined <i>in silico</i> and <i>in vitro</i> findings highlight the potential of these indazole-based compounds as dual-acting agents for treating multidrug-resistant tuberculosis and NSCLC. Further <i>in vivo</i> studies and mechanistic investigations are warranted to explore their clinical relevance.</p> Graphical abstract <p>It was demonstrated that the synthesized derivatives of 1H-indazole using HATU as a coupling agent showed promising antitubercular, analgesic, anti-inflammatory as well as anticancer activity. The compound NDM showed excellent biological activities.</p> <p></p>

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Design, synthesis and biological evaluation of 1H-indazole derivatives as InhA inhibitors and anticancer agents

  • 期刊论文

  • 发表日期：

    2026年2月20日

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  • R B Nanaware,
  • A R Chabukswar,
  • S C Jagdale,
  • R M Khobragade

摘要

A series of 1H-indazole derivatives were synthesized using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) as a coupling agent and evaluated for their dual biological activity against Mycobacterium tuberculosis (Mtb) and non-small cell lung cancer (NSCLC). Molecular docking and molecular dynamics (MD) simulations identified (2,5-dimethoxyphenyl)-(5-nitro-1H-indazol-1-yl)methanone (compound 11) was the most promising candidate, showing stable binding to the InhA enzyme with a binding energy of −9.76 kcal/mol. Compound 11 exhibited strong antitubercular activity (MIC 3.2 µg/mL), potent cytotoxicity against A549 cancer cells (78.45%), and significant anti-inflammatory effect (92.98% edema inhibition at 12h). Other derivatives also demonstrated noteworthy antimycobacterial and anti-inflammatory properties. Molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamic simulation (MDS) supported the favourable binding affinities and complex stability of the lead compound. Absorption, distribution, metabolism, and excretion (ADME) predictions confirmed drug-likeness with good gastrointestinal absorption and no violations of Lipinski's rule. The combined in silico and in vitro findings highlight the potential of these indazole-based compounds as dual-acting agents for treating multidrug-resistant tuberculosis and NSCLC. Further in vivo studies and mechanistic investigations are warranted to explore their clinical relevance.

Graphical abstract

It was demonstrated that the synthesized derivatives of 1H-indazole using HATU as a coupling agent showed promising antitubercular, analgesic, anti-inflammatory as well as anticancer activity. The compound NDM showed excellent biological activities.