Thiazolidinedione–Pyrazolopyrimidinone Molecular Hybrids With Alkyl Spacers: Potential Antitubercular Agents Complemented by Molecular Modeling

ABSTRACT

Mycobacterium tuberculosis ( Mtb ) remains a major global health threat and is the leading cause of death from a single infectious pathogen. The growing prevalence of drug‐resistant strains, together with the severe side effects of current antitubercular regimens, poses significant challenges to effective treatment and eradication of the disease. This underscores the urgent need to develop new antitubercular agents with enhanced efficacy. Herein, we report the synthesis of 21 novel thiazolidinedione–pyrazolopyrimidinone derivatives ( 12a–u ), which were obtained via coupling thiazolidinedione ( 5a–g ) and pyrazolopyrimidinone pharmacophoric units ( 11a–c ) through different alkyl chain linkers. The synthesized compounds were characterized using different spectroscopic techniques and subsequently evaluated in vitro for their antimycobacterial activity against Mtb  H37Rv strain, disclosing two potent compounds ( 5c and 5d ) with MIC ₉₀ < 0.24 µM. Molecular docking studies revealed that these compounds interacted with critical amino acid residue (Tyr158) of InhA and NAD co‐factor via hydrogen bonding. Furthermore, in silico toxicity predictions suggest that compounds 5c and 5d are noncarcinogenic and non‐hepatotoxic.