Background: To overcome one of the resistance mechanisms of Isoniazid (INH), there is a need
for an antitubercular agent that can inhibit InhA enzyme by circumventing the formation of INH-NAD+
Objective: The objective of the study is the development of novel antitubercular agents that target Mycobacterium
tuberculosis InhA (Enoyl Acyl Carrier Protein Reductase).
Methods: A small-molecule chemical library was used for the identification of the novel InhA inhibitors
using primary screening and molecular docking studies followed by the scaffold hopping approach. The
designed molecules, 2-(2-(hydroxymethyl)-1H- benzo[d] imidazole-1-yl)- N- substituted acetamides were
synthesized by reacting (1H- benzo[d]imidazole -2-yl)methanol with appropriate 2-chloro-N-substituted
acetamides / dialkylamino carbonyl chlorides respectively in good yields (42-65%). The antitubercular activity
of synthesized compounds was determined by Microplate Alamar Blue Assay (MABA) against Mycobacterium
tuberculosis H37Rv strain. The selected compounds were screened for cytotoxicity on normal
Results: The antitubercular activity data revealed that the 4-chlorophenyl substituted derivative (3b)
showed good MIC value at 6.25 μg/mL and, dimethylacetamide substituted derivative (3i) showed MIC at
25 μg/mL among the tested compounds. The substitution of dimethylacetamide (3i) group on the 1st position
of benzimidazole has good antitubercular activity (25μg/mL) in comparison to the diethyl acetamide
group (3j, 100μg/mL).
Conclusion: The antitubercular activity data indicated that the tested compounds exhibited well to moderate
inhibition of the H37Rv strains. The compounds (3b) with electronegative substitution on the phenyl
moiety exhibited better antitubercular activity than that of the other substitutions. The active compounds
have displayed a good safety profile on normal cell lines.