1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities

Presently, dual targeting by a singlesmall moleculestands outas an effective cancer-fighting weapon. Carbonic anhydrase (CA) andvascular-endothelial growth factor (VEGF) are hypoxia-activatablegenes that are implicated in tumorigenesis and progression of hypoxictumors at different levels. Herein, we designed and synthesized 301,5-diaryl-1,2,4-triazole-tethered sulfonamides (11a-f, 12a-l, 13a-f, 15a-f) asnovel SLC-0111 analogues with dual CA IX/XII and VEGFR-2 inhibitoryactivities. The 4-fluorophenyl SLC-0111 tail was replaced by substituted1,5-diaryl-1,2,4-triazoles. Changing the sulfamoyl motif positionprovided regioisomers 11a-f and 12a-l. Elongation of the ureido linkeryielded derivatives 15a-f. Inhibitoryevaluations included a panel of hCAs (hCA I, II, IX, and XII) and screening against 60 cancer cell lines.Promising candidates were assessed for VEGFR-2 inhibition and selectivityand further evaluated on breast cancer cell lines (MCF-7 and T-47D)and the non-tumorigenic (MCF-10A) cells. Molecular docking studiesexplored the binding modes of the sulfonamides against hCA IX/XII and VEGFR-2 kinase.