Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2)

Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure–Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1–3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level.

A combination of different approaches led to the disclosure of new thienopyrimidines as inhibitors of KDR activity and HUVEC proliferation. Compound 2f shows good inhibitory activity results and blocks angiogenesis of HUVEC at μM level.Figure optionsDownload as PowerPoint slideHighlights
► A series of new thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine has been synthesized.
► The compounds were found active against VEGFR-2 as designed by SBDD and LBDD approaches.
► The actions against HUVEC proliferation and endothelial cell tube formation were also investigated.
►  The most interesting derivative 2f is a new lead compound as potential anti-angiogenic drug.