4-(5-Chloro-3-(3,4,5-trimethoxybenzoyl)-1H-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.

ABSTRACT: 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 cance

SUBMITTER: Puxeddu M 

PROVIDER: S-EPMC12935169 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature