Structure-based design, synthesis, computational screening and biological evaluation of novel pyrrole fused pyrimidine derivatives targeting InhA enzyme

Abstract

In this study, a series of 12 novel pyrrolyl chalcones and 22 pyrrole-fused pyrimidine derivatives were synthesized with good yields. Structural characterization was performed using FT-IR, NMR, and mass spectrometry techniques. The antitubercular potential of these compounds was evaluated using the microplate alamar blue assay (MABA). Among the synthesized compounds, compound 4g exhibited the highest potency, with a minimum inhibitory concentration (MIC) of 0.78 mg mL⁻¹ demonstrating greater efficacy than the standard drug isoniazid. Several other analogues also showed moderate to good inhibitory activity. Selected compounds were further assessed for cytotoxicity using human lung cancer (A549) and normal RAW cell lines, revealing low toxicity profiles. Enzymatic assays indicated that compound 4g achieved 36% inhibition of InhA at a concentration of 50 μM. Additionally, molecular dynamics simulations were conducted to analyze the stability of the protein–ligand complexes, suggesting that these compounds hold potential for future development as InhA inhibitors in the fight against MDR-TB.