Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action

Mohamed Fares; Wagdy M Eldehna; Silvia Bua; Cecilia Lanzi; Laura Lucarini; Emanuela Masini; Thomas S Peat; Hatem A Abdel-Aziz; Alessio Nocentini; Paul A Keller; Claudiu T Supuran

doi:10.1021/acs.jmedchem.9b02090

Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action

J Med Chem. 2020 Mar 26;63(6):3317-3326. doi: 10.1021/acs.jmedchem.9b02090. Epub 2020 Feb 20.

Authors

Mohamed Fares^{1

2}, Wagdy M Eldehna³, Silvia Bua⁴, Cecilia Lanzi⁵, Laura Lucarini⁵, Emanuela Masini⁵, Thomas S Peat⁶, Hatem A Abdel-Aziz⁷, Alessio Nocentini⁴, Paul A Keller¹, Claudiu T Supuran⁴

Affiliations

¹ School of Chemistry & Molecular Bioscience, Molecular Horizons, and Illawarra Health & Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
² School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt.
⁴ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
⁵ Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50100 Florence, Italy.
⁶ Biomedical Manufacturing Program, CSIRO, 343 Royal Parade, Parkville, VIC 3052, Australia.
⁷ Department of Applied Organic Chemistry, National Research Center, Dokki, Giza 12622, Egypt.

PMID: 32031797
DOI: 10.1021/acs.jmedchem.9b02090

Abstract

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (K_i in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / therapeutic use*
Carbonic Anhydrases / chemistry
Carbonic Anhydrases / metabolism*
Catalytic Domain
Crystallography, X-Ray
Drug Design
Glaucoma / drug therapy*
Humans
Intraocular Pressure / drug effects*
Male
Molecular Structure
Protein Binding
Rabbits
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / metabolism
Sulfonamides / therapeutic use*

Substances

Carbonic Anhydrase Inhibitors
Sulfonamides
Carbonic Anhydrases