Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

Chemistry of Natural Compounds Department Pharmaceutical and Drug Industries Research Institute National Research Center Dokki Cairo 12622 Egypt

Department of Medical Physiology College of Medicine King Khalid University Asir 61421 Saudi Arabia

Department of Molecular Microbiology Faculty of Biology and Environmental Protection University of Lodz Lodz Poland

Department of Pharmaceutical Chemistry Faculty of Pharmacy Kafrelsheikh University Kafrelsheikh P O Box 33516 Egypt

Department of Pharmaceutical Sciences College of Pharmacy AlMaarefa University Riyadh 13713 Saudi Arabia

Institute of Chemistry Vietnam Academy of Science and Technology 18 Hoang Quoc Viet Caugiay Hanoi 10000 Viet Nam

Institute of Natural Products Chemistry VAST 18 Hoang Quoc Viet Caugiay Hanoi 10000 Viet Nam

Institute of Organic Chemistry and Biochemistry Academy of Sciences Prague Czech Republic

Laboratory of Genetics and Physiology of Mycobacterium Institute of Medical Biology of the Polish Academy of Sciences Lodz Poland

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