Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR

Abstract

A metal-free, atom-economy and simple work-up domino amination-Knoevenagel condensation approach to construct new coumarin analogous (<b>4a-f</b> and <b>8a-e</b>) was described. Further, new formyl (<b>5a,d-f</b>) and nitro (<b>9a,d-f</b>) coumarin derivatives were synthesized via C-N coupling reaction of various cyclic secondary amines and 4-chloro-3-(formyl-/nitro)coumarins (<b>1a,c</b>), respectively. The confirmed compounds were screened for their <i>in vitro</i> anti-proliferative activity against KB-3-1, A549 and PC3 human cancer cell lines using resazurin cellular-based assay. Among them, coumarin derivatives <b>4e</b> and <b>8e</b> displayed the best anti-cervical cancer potency (KB-3-1) with IC₅₀ values of 15.5 ± 3.54 and 21 ± 4.24 μM, respectively. Also, <b>4e</b> showed the most promising cytotoxicity toward A549 with IC₅₀ value of 12.94 ± 1.51 μM. As well, <b>9d</b> presented a more significant impact of potency against PC3 with IC₅₀ 7.31 ± 0.48 μM. Moreover, <b>8d</b> manifested selectivity against PC3 (IC₅₀ = 20.16 ± 0.07 μM), while <b>8e</b> was selective toward KB-3-1 cell line (IC₅₀ = 21 ± 4.24 μM). Matching with docking profile, the enzymatic assay divulged that <b>8e</b> is a dual potent single-digit nanomolar inhibitor of VEGFR-2 and EGFR with IC₅₀ values of 24.67 nM and 31.6 nM that were almost equipotent to sorafenib (31.08 nM) and erlotinib (26.79 nM), respectively.