4‐(5‐Chloro‐3‐(3,4,5‐trimethoxybenzoyl)‐1 <i>H</i> ‐indol‐1‐yl)benzenesulfonamide: A Novel Polypharmacology Agent to Target Carbonic Anhydrase IX and XII With Improved Selectivity, Wnt/β‐Catenin Signaling Pathway, and P‐Glycoprotein

We synthesized novel pyrrole (5-11) and indole (12-16) derivatives based on a polypharmacology approach aimed to obtain inhibitors of human carbonic anhydrase (hCA) with improved selectivity toward the IX and XII isoforms, Wnt/β-catenin pathway, and P-glycoprotein (P-gp). Inspection of the binding sites of the hCA I, II, IX, and XII isoforms highlighted small but significant differences of cavity volumes that guided the introduction of small substituents at Position 4 of the 3-phenyl ring of the pyrrole and at Position 5 of the indole. Compound 15 exhibited potent and selective inhibition of both hCA IX and XII isoforms compared to the parent compound. It inhibited the Wnt/β-catenin pathway abrogating the association of β-catenin with TCF-4 and the multidrug-resistant P-gp-expressing cancer cells. Compound 15 showed strong inhibition of viability of SW620, SW480, and HCT116 CRC and TNBC cell lines, restored the sensitivity to doxorubicin (DOX) in HT29/DX P-gp-overexpressing cells, and showed medium metabolic stability in both human and mouse microsomes and acceptable predicted oral bioavailability. Compound 15 is a robust lead compound for the development of new antitumor agents based on the polypharmacology approach.