DESIGN, DOCKING AND SYNTHESIS OF NOVEL BROMO ISATIN INCORPORATED ISOXAZOLE DERIVATIVES AS VEGFR-2 INHIBITORS
- Vol.11(4)
- M P Innovare Academic Sciences Pvt Ltd 2019
- 1-7p.
Objective: To design, synthesize, in vitro Vascular Endothelial Growth Factor Receptor (VEGFR -2) assay, antiproliferative activity an Absorption , Distribution, Metabolism, Excretion and Toxicity (A DMET) studies of some novel bromoisatin incorporate d isoxazole derivatives. Methods: Designed compounds were synthesized by the condensa tion of different 3-aryl-5-methylisoxazole-4-carboh ydrazides (5a-h) with 5-bromoisatin to give the target molecules. To predict the affini ty and activity of the ligand molecule the docking program GOLD 3.1 was employed to generate different bioactive binding poses of designing molecules at t he active site of protein VEGFR-2. All the synthesi zed compounds were characterized based on the spect ral and elemental analysis data. Antiproliferative acti vity performed against Human Umbilical vein endothe lial cells (HUVEC cell line). Results: All the synthesized compounds showed the characteri stic peaks in FTIR, 1 H, C 13 NMR and Mass spectral analysis. In molecular dockin g, all the synthesized compounds (6a-j) exhibited high fit ness scores with minimum three bonding interaction with the active site VEGFR-2 kinase. In in- vitro , VEGFR-2 kinase assay, compounds 6a, 6b, 6d and 6e exhibited more than 70% inhibition at a single dos e concentration of 5μM. In antiproliferative assay against HUVEC cell lines, co mpounds 6d and 6e exhibited potent activity with IC 50 values in nanomolar concentrations. ADMET results of 6a, 6b, 6d and 6e are quite promis ing with least hepatotoxicity and good bioavailabil ity. Conclusion: The derivatives were synthesized in quantitative yi elds. New derivatives posses antiproliferative acti vity, least hepatotoxicity and good bioavailability.