Synthesis of hydrophobic N-acylated isonicotinic acid hydrazide derivatives as potential enoyl-acyl carrier protein reductase (InhA) inhibitors

Enoyl-acyl carrier protein reductase (InhA) is an important enzyme for the biosynthesis of mycolic acids which are central constituents of the mycobacterium cell wall. In the present study, we synthesized, characterized hydrophobic N-acylated isonicotinic acid hydrazide derivatives (2a-2m) as potential enoyl-acyl carrier protein reductase (InhA) inhibitors and tested them against Mycobacterium tuberculosis H37Rv and two human clinical isolates by means of colorimetric tetrazolium micro-plate assay. Compounds 2c-2m displayed good-to-excellent inhibitory activity against all tested strains as compared with isoniazid. In vivo acute toxicity studies were performed by Up-and-Down procedure. The results showed that all the tested compounds were non-toxic and well tolerated considering their LD50 values ranging from 3,898 to 5,000 mg/kg body weight.