Synthesis and discovery of direct Enoyl-ACP Reductase (InhA) inhibitors via in-silico studies and ADMET prediction for potent anti-tubercular activity

<title>Abstract</title> <p> The increase in multidrug-resistant tuberculosis (MDR-TB) is mainly due to a mutation in the katG gene, which prevents activation of standard pro-drugs like Isoniazid, and is a critical challenge for global health. To overcome this issue, direct inhibition of Enoyl-ACP reductase (InhA) is an excellent option for therapeutic target. Here in, a series of ten novel triazolopyrimidines (VP101-VP110) were synthesized for evaluation of <italic>in-silico</italic> analysis as InhA inhibitor, in which compounds VP107 and VP109 demonstrated extraordinary binding energies of −13.93 kcal/mol, and closely followed at −13.14 kcal/mol respectively, with picomolar inhibition constant outperforming the standards Triclosan (−8.67 kcal/mol) and Ethambutol (−7.15 kcal/mol). Mechanistically, these compounds act as Direct InhA Inhibitors (DIIs) in their native state, avoiding the necessity of KatG activation. The ADMET profiling advocated favourable drug-likeness, compliance with Lipinski’s Rule of Five, excellent intestinal absorption, high plasma protein binding (&gt;94%), and minimal blood-brain barrier penetration. However, hepatotoxicity and genotoxicity across the series were a matter of concern. Ultimately, the synthesised compounds show exceptionally potent direct-acting therapeutic drugs, especially VP107, which can act as a lead for evading traditional katG-mediated resistance vectors in tuberculosis treatment. </p>