Potential VEGFR-2 inhibitors based on the molecular structures of imidazo[2,1-b]thiazole and matrine: Design, synthesis, in vitro evaluation of antitumor activity and molecular docking

Abstract

Some novel imidazo[2,1-b]thiazole-matrine derivatives have been obtained by utilizing a scaffold splicing strategy based on a lead compound, matrine, which has good cancer therapeutic potential, and an imidazo[2,1-b]thiazole scaffold, which has good VEGFR-2 inhibitory activity, which aimed to discover potential VEGFR-2 inhibitors. Notably, compounds 6H and 7H showed great antiproliferative activity against HGC-27 cells with IC₅₀ values of 9.26 and 7.04 μM, respectively, and comparable in activity to the multi-targeted small molecule inhibitor sorafenib. 6H was shown to have a favourable inhibition rate against VEGFR-2(IC₅₀ = 3.09 ± 0.15 μM) with low toxicity to normal cells.The 3D-QSAR analysis further elucidates the relationship between derivative structure and antiproliferative activity. Docking studies revealed the ability of compounds 6H, and 7H to bind to the hinge region of the target binding site, thus supporting the experimental inhibition results. Furthermore, the developed compounds induced apoptosis and induced cell cycle G₀/G₁ phase arrest. This study demonstrated that 6H is a potential VEGFR-2 inhibitor and informs the development of anti-gastric cancer drugs.