New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies. Issue 5 (1st March 2020)

• Record Type: Journal Article
• Authors: Abdel-Mohsen, Heba T.; El Kerdawy, Ahmed M.; Omar, Mohamed A.; Berrino, Emanuela; Abdelsamie, Ahmed S.; El Diwani, Hoda I.; Supuran, Claudiu T.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 5(2020)
• Publication Date: 2020-03-01
• Subjects: Synthesis -- Thiopyrimidine-benzenesulfonamide conjugates -- Carbonic anhydrase -- Molecular docking; 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.2020.115329
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A new series of thiopyrimidine-benzenesulfonamide conjugates was synthesized and evaluated for their CA inhibitory activity. Compounds 6a–g displayed promising inhibitory activity against cytosolic isoforms hCA I and hCA II. Compounds 6e and 6f showed Ki of 0.04 µM against hCA II. Compounds 6e and 6f demonstrated selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking simulations of 6a–g with hCA II revealed key H-bonding interactions with the sulfonamide group and hydrophobic interactions with the benzenesulfonamide and thiopyrimidine moieties. Abstract: In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed Ki of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn 2+ ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs.