Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors.

[Display omitted] • Triazole-quinoxaline hybrids were crafted as dual VEGFR-2 /MAO-B inhibitors for halting CRC. • 11 and 14 surpassed 5-FU against HCT-116 cells regarding potency and selectivity. • 14 recorded one-digit nanomolar IC 50 concentration against VEGFR-2. • 11 was superior to the reference MAOI methylene blue with MAO-B/A selectivity. • 11 and 14 downregulated HIF-1α in HCT-116 cells and inhibited their migration by >75 %. Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H -tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC 50 = 18.04 and 7.850 µM, respectively, against HCT-116 cells within their EC 100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC 50 = 88.79 and 9.910 nM), MAO-A (IC 50 = 0.763 and 629.1 nM) and MAO-B (IC 50 = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116 cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics. [ABSTRACT FROM AUTHOR]