Design, synthesis, and anti-mycobacterial evaluation of 1,8-naphthyridine-3-carbonitrile analogues.

Twenty-eight compounds, viz. , 1,8-naphthyridine-3-carbonitrile (ANC and ANA) derivatives, were designed and synthesized through a molecular hybridization approach. The structures of these compounds were analyzed and confirmed using 1 H NMR, 13 C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated by in vitro testing for their effectiveness against tuberculosis using the MABA assay, targeting the Mycobacterium tuberculosis H37Rv strain. Their minimum inhibitory concentration (MIC) was determined, showing that the tested compounds' MIC values ranged from 6.25 to ≤50 μg mL -1 . Among the derivatives studied, ANA-12 demonstrated prominent anti-tuberculosis activity with a MIC of 6.25 μg mL -1 . Compounds ANC-2, ANA-1, ANA 6-8, and ANA-10 displayed moderate to good anti-tuberculosis activity with MIC values of 12.5 μg mL -1 . Compounds with MIC ≤ 12.5 μg mL -1 were screened against human embryonic kidney cells to assess their potential cytotoxicity. Interestingly, these compounds showed less toxicity towards normal cells, with a selectivity index value ≥ 11. To further evaluate the binding pattern in the active site of enoyl-ACP reductase (InhA) from Mtb (PDB-4TZK), a molecular docking analysis of compound ANA-12 was performed using the glide module of Schrodinger software. The stability, confirmation, and intermolecular interactions of the cocrystal ligand and the highly active compound ANA-12 on the chosen target protein were investigated through molecular dynamics simulations lasting 100 ns. In silico predictions were utilized to assess the ADMET properties of the final compounds. A suitable single crystal was developed and analyzed for compound ANA-5 to gain a deeper understanding of the compounds' structures.