Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition. (26th April 2022)

• Record Type: Journal Article
• Authors: Bozdag, Murat; Cravey, Lochlin; Combs, Jacob; Kota, Anusha; McKenna, Robert; Angeli, Andrea; Selleri, Silvia; Carta, Fabrizio; Supuran, Claudiu T.
• Is Part Of: ChemMedChem. Volume 17:Number 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-26
• Subjects: Carbonic anhydrase inhibitors (CAIs) -- X-ray crystallography -- Structure-activity relationships (SARs) -- Isoform selectivity; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200148
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: We report aryl sulfonamide inhibitors of human carbonic anhydrase (hCA; EC 4.2.1.1) enzymes containing short ureido alkoxy tails. The inhibition potency of such compounds was investigated in vitro on the major hCA isoforms (i.e. I, II, IX, and XII). A selection of the most potent inhibitory derivatives against the hCA IX isoform (i.e. 5a, 5c, and 6c) was studied, and their binding modes on either hCA II and IX‐mimic isoform were assessed by X‐ray crystallography on the corresponding ligand/protein adducts. This study adds to the field of developing hCA inhibitors at molecular level the critical interactions governing ligand selectivity. Abstract : Selectivity drivers : We report in‐depth details about the binding modes of a series of alkoxy‐containing ureido benzenesulfonamides within human carbonic anhydrase II and IX isoform mimics. These were used as orthosteric probes to decipher the structural determinants responsible for driving isoform selectivity.