Exploring new Probenecid-based carbonic anhydrase inhibitors: Synthesis, biological evaluation and docking studies. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Mollica, Adriano; Costante, Roberto; Akdemir, Atilla; Carradori, Simone; Stefanucci, Azzurra; Macedonio, Giorgia; Ceruso, Mariangela; Supuran, Claudiu T.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5311
• Page End: 5318
• Publication Date: 2015-09-01
• Subjects: Probenecid -- Selective carbonic anhydrase IX inhibitors -- Selective carbonic anhydrase XII inhibitors -- Tertiary sulfonamides -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.066
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Novel Probenecid-based amide derivatives, incorporating different natural amino acids, were synthesized and assayed to test their effect on the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII over the ubiquitous isoforms hCA I and II. Most of them presented a complete loss of hCA II inhibition (Ki s >10, 000 nM) and strong inhibitory activity against hCA IX and XII in the nanomolar range with respect to the parent compound. A residual activity against hCA I was observed for some of them. These biological results have been explained by docking studies within the active sites of the four studied human carbonic anhydrases (with or without the zinc-bound water) and helped us to better comprehend the rationale behind the design of tertiary sulfonamide compounds as potent but atypical inhibitors of specific isoforms of human carbonic anhydrase.