Design, Synthesis and Docking Study of Some Novel Isatin- Quinoline Hybrids as Potential Antitubercular Agents

Background: Tuberculosis (TB) is the one which remains the world’s greatest public health challenges. Worldwide resurgence of TB is due to two major problems: the AIDS epidemic and the outbreak of multidrug resistant (MDR) TB. Thus, there is an urgent need to develop anti-TB drugs with enhanced activity against MDR strains. In the present study a hybrid pharmacophore based approach was used to design and synthesize Isatin - quinoline hybrids. All the new series of hybrids (5a-j & 6a-l) were investigated for molecular docking study against enoyl ACP reductase enzyme. Methods: The docking study was performed on 22 newly designed isatin analogs on the active site of crystal structure of enoyl-ACP reductase enzyme (PDB ID: 4TZK). The binding modes of these analogs were calculated based on the two parameters such as binding energy and inhibition constant. Isatin- quinoline hybrid molecules were synthesized and characterized by various well known physical and spectral analyses (FT-IR, 1H-NMR and Mass spectroscopy). Results: According to the docking study compound 6h has highest binding affinity with a binding energy of -9.08 kcal/mol and predicted inhibition constant is 221.75 nanomolar. This compound exhibited well established hydrophobic bonds with amino acid Tyr 158 and the co factor NAD 500 in the receptor active pocket and fortunately these two are responsible for the enzyme activity. Further, in vitro antitubercular activity has been performed for all the hybrids against drug resistant strains of Mycobacterium tuberculosis (M.tb) using microdilution assay and their minimum inhibitory concetration (MIC) was determined. Compound 6h has the good inhibitory (0.09 μM) activity as compared to the reference drug, isoniazide (0.03 μM). Conclusion: The enhanced activity of the compound 6h against poly and multi drug resistant strains is due to the presence of electron withdrawing groups on the aromatic ring of isatin.