Synthesis of novel 2‐acetamide‐5‐phenylthio‐1,3,4‐thiadiazole‐containing phenyl urea derivatives as potential VEGFR‐2 inhibitors

Abstract

A novel series of 2‐acetamide‐5‐phenylthio‐1,3,4‐thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT‐29, A431, and PC3, as well as normal HDF cells, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4‐chloro‐containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl‐2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR‐2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three‐dimensional cell culture method using the hanging drop technique.

Computational insights into novel benzenesulfonamide-1,3,4-thiadiazole hybrids as a possible VEGFR-2 inhibitor: design, synthesis and anticancer evaluation with molecular dynamics studies

“…32 Moreover, the sorafenib-derived compound V inhibited VEGFR-2 in A431 cancer cell lines, and its molecular modeling illustrated the interaction of the thiadiazole ring with Val848, Ala866, and Leu1035. 33 Recently reported benzenesulfonamide derivatives VI and VII inhibited VEGFR-2 with an IC 50 of 23.10 nM and 30.10 nM, respectively. 34…”

“…32 Moreover, the sorafenib-derived compound V inhibited VEGFR-2 in A431 cancer cell lines, and its molecular modeling illustrated the interaction of the thiadiazole ring with Val848, Ala866, and Leu1035. 33 Recently reported benzenesulfonamide derivatives VI and VII inhibited VEGFR-2 with an IC 50 of 23.10 nM and 30.10 nM, respectively. 34 The design of the proposed derivatives relied on the established pharmacophore features obtained from sorafenib 10 while acknowledging the presence of benzenesulfonamide where the co-crystallized ligand is shown as a green ball model, and the catalytic site, the DFG-motif, and the hinge region are in red, magenta and blue, respectively.…”