Abstract

The current investigation involves design, synthesis, and assessment of the potential antimycobacterial activity of three sets of 4,4-diphenylimidazolidinone-2-hydrazone derivatives, 3a-l, 4a-h, and 5a,b. Their In vitro efficacy against M. smegmatis ATCC 607 was assessed versus isoniazid (INH) as reference drug. The results revealed that, ten of the tested compounds exhibited inhibitory ability analogous to INH, with MIC values ranging from 0.032 to 0.45 µM (INH: 0.046 µM). Explicitly, the p-tolylethylidene hydrazone 4c and the 2-oxoindoline-3-ylidene 5a are the most potent compounds (MIC = 0.033 µM). Compound 5a exhibited bactericidal effect equivalent to INH, as evidenced by the time-kill kinetics pattern (≥ 3 log reduction in bacterial count: 99.9 % killing), at 4x MIC value, after 72 h of incubation. Cytotoxicity assessment of the most potent compounds, 4a,c,e, 5a,b, against Vero cells line, revealed minimal in vitro cytotoxicity (SI ~ 40 - > 2000). Bioactivity profiling analysis using several computational and inverse molecular modeling approaches revealed that the studied compounds exhibit multitarget potential as antimycobacterials. The results indicate that mycobacterial acyl-carrier-protein reductase (InhA) is the most credible potential target. Molecular docking studies in the active site of ACP reductase (InhA) revealed promising interaction with the catalytic triad amino acid residues, Tyr 158, Lys165, and phe149. Computational assessment of the molecular characteristics and drug-like scores demonstrate prospective eligibility for further assessments as new series of antimycobacterial agents. The attained results suggest that the studied arylidene hydrazinylimidazolidinones be worthy for further optimization for antimycobacterial activity.