Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases.

Majid Ali,Murat Bozdag,Claudiu T Supuran,Giuseppe Zanotti,Andrea Angeli,Fabrizio Carta,Paola Berto,Umar Farooq

doi:10.3390/ijms21072560

Abstract

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

Highlights

Carbonic anhydrases (CA, EC 4.2.1.1) are a ubiquitous superfamily of metalloenzymes present in all living organisms
In this study we further extended our research by means of designing and synthesizing sulfonamide based carbonic anhydrase inhibitors (CAIs) possessing the benzylaminoethylureido-tails, not reported yet, and we investigated their inhibition profiles in vitro against the physiologically dominant cytosolic human carbonic anhydrases (hCA) I and II and the tumor associated isoforms hCA IX and XII with the aim to set the basis for a preliminary structure-activity relationship (SAR) worthy of future development
Our drug design strategy was based on a multistep synthesis, based on the methodology previously reported for obtaining 4-N-substituted piperazinyl-ureido benzene sulfonamides [32]

Summary

Introduction

Carbonic anhydrases (CA, EC 4.2.1.1) are a ubiquitous superfamily of metalloenzymes present in all living organisms. Fifteen carbonic anhydrase isozymes have been characterized in humans and they all mainly differ for their catalytic activities, subcellular localizations and tissue distributions [1,2,3,4]. The abnormal expression of one or multiple CA isoforms in humans usually is associated to various pathologies [4,5,6]. New evidences in the field strongly support the involvement of CA isoforms in other pathologies, such as neuropathic pain, arthritis, cerebral ischemia and pave the way for the use of CAIs in their management [11,12,13,14]

Methods

Results

Conclusion