Isoniazid-Dihydropyrimidinone Molecular Hybrids: Design, Synthesis, Antitubercular Activity and Cytotoxicity Investigations with Computational Validation.

In this study, we designed and synthesized a new series of  isoniazid-dihydropyrimidinone molecular hybrids (8a-8n). All compounds were structurally characterized using spectroscopic techniques viz., FTIR, NMR (1H, 13C, HMBC, and HSQC), and HRMS followed by their in vitro anti-tubercular evaluation including their precursors (4a-4n), and a standard anti-tubercular drug (Isoniazid; INH). The molecular hybrids particularly 8g (MIC = 6.25 µg/ml), 8h (MIC = 1.56 µg/ml), 8k (MIC = 0.78 µg/ml), 8l (MIC = 6.25 µg/ml), and 8n (MIC = 0.39 µg/ml) demonstrated the most potent inhibitory activity against wild-type M. tuberculosis mc26230, disclosing 8n as the most potent compound in the series. However, the potent compounds (8g, 8h, 8k, 8l, and 8n) which display low MIC values against wild-type strain lost their activity against three INH-resistant M. tuberculosis strains mutated in katG . The more efficient compounds (8h, 8k, and 8n) were subsequently evaluated for their cytotoxicity against the THP-1 human monocytic cell line. Furthermore, the stability studies of the most potent compound carried out using 1H NMR, UV-visible, and LCMS revealed their structural integrity.  Overall, these molecular hybrids have the potential to be developed as promising anti-tubercular agents after relevant structural modifications.