Novel Sulfamide-Containing Compounds as Selective Carbonic Anhydrase I Inhibitors

Emanuela Berrino,Gianluca Bartolucci,Vijayaparthasarathi Vijayakumar,Alessandro Mugelli,Fabrizio Carta,Mattia Mori,Yasinalli Tamboli,Vallabhaneni S Murthy,Maurizio Botta,Elisabetta Cerbai,Silvia Bua,Claudiu T Supuran

doi:10.3390/molecules22071049

Abstract

The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a β-alanyl or nipecotyl spacer. All compounds 6a–l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.

Highlights

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes belonging to the superfamily of metalloenzymes [1,2,3]
The aim aimofofthis thisstudy study was explore whether compounds bearing a sulfonamide bioisoster, The was to to explore whether compounds bearing a sulfonamide bioisoster, such such the sulfamide and installed into highly flexible alkyl-aryl scaffolds might as theas sulfamide and installed into highly flexible alkyl-aryl scaffolds might show a significant enhancement their selectivity theherein hCAsconsidered considered
We have reported the design and synthesis of 12 compounds bearing the sulfamide moiety as the zinc-binding-group (ZBG) and connected to a flexible tail section

Summary

Introduction

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes belonging to the superfamily of metalloenzymes [1,2,3]. Fifteen isoforms of these enzymes have been reported in humans, and they all differ for kinetic properties, sub-cellular localization and tissue distribution [1,2]. They all catalyze a simple as well as critical reaction, namely the reversible conversion of carbon dioxide to bicarbonate and protons [1,2]. These small molecules (carbon dioxide, protons and bicarbonate) are involved as natural substrates of many other enzymes of particular interest, such as sodium–bicarbonate co-transporters (NBCs), sodium–proton exchangers (NHEs) or chloride–bicarbonate exchanger (AEs) [4,5,6]. The ability to modulate the CA’s enzymatic activities by means of the use Molecules 2017, 22, 1049; doi:10.3390/molecules22071049 www.mdpi.com/journal/molecules use of small molecules as inhibitors or activators give to the pharmacological of small molecules actingacting as inhibitors or activators may givemay access to access the pharmacological treatment treatment of human diseases [7,8,9]

Methods

Discussion

Conclusion