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

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 (<b>11a</b>-<b>f</b>, <b>12a</b>-<b>l</b>, <b>13a</b>-<b>f</b>, <b>15a</b>-<b>f</b>) 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 <b>11a</b>-<b>f</b> and <b>12a</b>-<b>l</b>. Elongation of the ureido linker yielded derivatives <b>15a</b>-<b>f</b>. Inhibitory evaluations included a panel of <i>h</i>CAs (<i>h</i>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 <i>h</i>CA IX/XII and VEGFR-2 kinase.