Synthesis, structure analysis, DFT calculations and energy frameworks of new coumarin appended oxadiazoles, to regress ascites malignancy by targeting VEGF mediated angiogenesis

Abstract

Ascites malignancy is a frequent cause of morbidity and presents significant management problems which occur in many cancers. Angiogenesis plays a major role in the prognosis of ascites tumor through Vascular Endothelial Growth Factor (VEGF). Inhibition of VEGF is one of the key strategies in the regression of ascites tumor. The aim of the study is to synthesize a novel class of VEGF inhibitors for therapeutic intervention against ascites tumor malignancy. As an approach, a new series of 1, 3, 4-oxadiazole derivatives, containing coumarin-3-substituted aryl and heteroaryl moiety (7a-l) were synthesized in a multi-step process. The structures of these compounds were characterized by IR, 1H, 13C, NMR, mass spectra and elemental analyses. The newly synthesized molecules were subjected to cell-based screening against multiple cell lines such as ACHN, A375, SIHA, Skov3, and EAC through MTT and Trypan blue assay, and identified compound (7k) with IC50 -9 µM was identified as lead bioactive molecule. Further, VEGF induced non tumorigenic CAM and RAT corneal assay revealed angiopreventive efficacy of compound (7k). The in-vitro studies proved the inhibition of VEGF expression and relative MMP expression, and as a consequence, migration and invasion behavior were also altered. Further, the in-vivo ascites tumor model revealed VEGF mediated suppression of ascites malignancy without inducing any significant toxicological side effects. In conclusion, the compound (7k) has been identified as a new class of VEGF inhibitor which could be translated for therapeutic applications. Further the molecular geometry of potent compound (7k) has been obtained by density functional theory (DFT) using B3LYP/6–311 G (d,p) basis sets, and the spectra of FT-IR in the range of (400–4000 cm−1), HNMR and 13CNMR data were also computed and compared to the experiment data. Besides, frontier molecular orbitals (FMOs) through the investigation of highest occupied molecular orbitals (HOMO) and the lowest- unoccupied molecular orbitals (LUMO). The lowermost concentration of electron density on LUMO level compared to the HOMO level, as well as lesser energy gap value denote the ease of electrons transportation that reflecting higher reactivity of the compound (7k) compared to other compounds.