Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis

• Twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives.
• The compounds were screened for MTB InhA and anti-TB activities.
• Compound 21 showed IC50 of 3.12 μM against MTB InhA and MIC of 4.76 μM.

InhA, the enoyl acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel anti-tubercular agents. Twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives were synthesized and evaluated for their in vitro MTB InhA inhibition. Compounds were further evaluated for their in vitro activity against drug sensitive and resistant MTB strains and cytotoxicity against RAW 264.7 cell line. Compounds were docked at the active site of InhA to understand their binding mode and differential scanning fluorimetry was performed to ascertain their protein interaction and stability.

Compound 21 emerged as the most active compound with an IC50 of 3.12 μM against MTB InhA. It inhibited MTB with MIC of 4.76 μM and was non-cytotoxic at 100 μM.Figure optionsDownload as PowerPoint slide