2. Academic Validation
  3. Structure-activity relationship-driven lead optimization of pyrazole hydrazide-hydrazone analogues as potent antimycobacterial agents: in vitro and in silico studies

Structure-activity relationship-driven lead optimization of pyrazole hydrazide-hydrazone analogues as potent antimycobacterial agents: in vitro and in silico studies

  • Bioorg Med Chem Lett. 2026 Feb 26:136:130601. doi: 10.1016/j.bmcl.2026.130601.
Pardeep Kumar 1,  Anuradha Singampalli 1,  Rani Bandela 1,  Sri Mounika Bellapukonda 1,  Ramakrishna Kodi 1,  Subhendu Ghosh 1,  Laxma Naik Korra 1,  Aman Dalal 2,  Ankita Devi 2,  Nitin Pal Kalia 3,  Srinivas Nanduri 1,  Venkata Madhavi Yaddanapudi 4
Affiliations

Affiliations

  • 1 Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
  • 2 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India.
  • 3 Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India. Electronic address: nitin.kalia@niperhyd.ac.in.
  • 4 Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India. Electronic address: yssmadhavi@gmail.com.
PMID: 41759832 DOI: 10.1016/j.bmcl.2026.130601
Abstract

A distinct series of novel pyrazole hydrazide-hydrazone analogues, developed through a structure-activity relationship-driven lead optimization approach, and evaluated for their antitubercular activity. Among the evaluated compounds, within the series, compounds 5l and 5m demonstrated notable potency, with MIC values of 0.5 and 1 μg/mL, respectively, along with efficacy against drug-resistant Mycobacterium tuberculosis strains and favorable SI values 23-24. To elucidate the possible mechanism of action, the lead compounds were subjected to molecular docking and 100 ns molecular dynamics simulations, which strongly implicated enoyl-ACP reductase (InhA) as the most probable biological target. Furthermore, in silico ADME analysis revealed favorable pharmacokinetic properties and drug-likeness profiles for the most active derivatives. Collectively, these results highlight the potential of these novel pyrazole hydrazide-hydrazone scaffolds as promising lead candidates for the development of next-generation antitubercular agents, particularly against drug-resistant strains.

Keywords

Drug resistance; In silico studies; Mycobacterium tuberculosis; Pyrazole; Tuberculosis.

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