1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities
Ahmed E. Elsawi, Mostafa M. Elbadawi, Alessio Nocentini, Hadia Almahli, Simone Giovannuzzi, Moataz A. Shaldam, Rofaida Salem, Tamer M. Ibrahim, Hatem A. Abdel‐Aziz, Claudiu T. Supuran, Wagdy M. Eldehna
Abstract
Presently, dual targeting by a single small molecule stands out as an effective cancer-fighting weapon. Carbonic anhydrase (CA) and vascular-endothelial growth factor (VEGF) are hypoxia-activatable genes that are implicated in tumorigenesis and progression of hypoxic tumors at different levels. Herein, we designed and synthesized 30 1,5-diaryl-1,2,4-triazole-tethered sulfonamides ( 11a – f, 12a – l, 13a – f, 15a – f ) as novel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitory activities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted 1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif position provided regioisomers 11a – f and 12a – l . Elongation of the ureido linker yielded derivatives 15a – f . Inhibitory evaluations included a panel of h CAs ( h CA I, II, IX, and XII) and screening against 60 cancer cell lines. Promising candidates were assessed for VEGFR-2 inhibition and selectivity and further evaluated on breast cancer cell lines (MCF-7 and T-47D) and the non-tumorigenic (MCF-10A) cells. Molecular docking studies explored the binding modes of the sulfonamides against h CA IX/XII and VEGFR-2 kinase.