Design, synthesis, in vitro antiproliferative evaluation and in silico studies of new VEGFR-2 inhibitors based on 4-piperazinylquinolin-2(1H)-one scaffold

Abstract

Angiogenesis is essential in the growth of solid tumors which need oxygen and nutrients supply to grow in size. The VEGF/VEGFR-2 signaling pathway plays an important role in tumor angiogenesis. Sorafenib is an FDA approved cancer therapeutic with activity against many protein kinases, including VEGFR. We designed 4-piperazinylquinolin-2(1H)-ones with variable aromatic moieties and Mannich bases as Sorafenib analogues as potential inhibitors of angiogenesis. In this study, we investigated the impact of replacing the linker aromatic ring with cyclic tertiary amines and the effect of incorporation of variably substituted distal rings. We hypothesized that cyclic tertiary amines would improve pharmacokinetic properties and contribute to enzyme interactions. Two series of piperazinylquinolinone-based compounds were synthesized, characterized, and evaluated for bioactivity against adenocarcinoma EKVX NSCLC and T-47D breast cancer cells. Ability to inhibit VEGFR-2 and apoptosis were investigated and molecular docking into the enzyme active site and theoretical ADME properties were determined. Notably, amongst series I three compounds exhibited higher anticancer activity than Staurosporine against EKVX NSCLC adenocarcinoma cell line. In series II, nine compounds exhibited higher antiproliferative activity than Staurosporine against T-47D breast cancer cell line. Two compounds; 5d and 7z exhibited lower toxicity against normal cell line (MCF 10A) than Staurosporine. Compound 7z was the most potent agent with IC₅₀ 38.76 nM. Moreover, 7z showed VEGFR-2 inhibitory activity higher than sorafenib and induced remarkable levels of both early and late apoptosis (2.82% and 21.30%, respectively). Hence, 5d and 7z are considered promising VEGFR-2 inhibitors with high efficacy against adenocarcinoma EKVX and T-47D breast cancer cells. The target compounds also possessed favorable physicochemical properties and pharmacokinetic parameters These studies further suggested that the 4-piperazinylquinolin-2(1H)-one derivatives developed in this study play a critical role in modulating VEGFR, and guide the design of innovative anticancer therapies.

Keywords: 4-Piperazinylquinolin‐2(1H)-one; Angiogenesis, ADME; Breast cancer; Mannich bases; NSCLC; VEGFR‐2 inhibitors.