Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV

Abstract

A set of sulfamides and sulfamates were synthesized and tested against several isoforms of carbonic anhydrase: CA I, CA II, CA VII, CA XII and CA XIV. The biological assays showed a broad range of inhibitory activity, and interesting results were found for several compounds in terms of activity (Ki <1μm) and selectivity: some aromatic sulfamides are active against CA I, CA II and/or CA VII; while they are less active in CA XII and CA XIV. On the other hand, bulky sulfamides are selective to CA VII. To understand the origin of the different inhibitory activity against each isozyme we used molecular modeling techniques such as docking and molecular dynamic simulations.

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

“…Plenty of studies has been reported showing that many sulphamates possess effective inhibitory properties against all known human isoforms 1,11,[16][17][18][19] , with some derivatives, such as the sugar sulphamate topiramate (compound 1 in Figure 1), successfully used for the treatment of a variety of diseases such as epilepsy, migraine, and obesity 20,21 . Although the sulphamide group was initially considered not particularly suitable for obtaining potent CAIs 22 , several compounds containing a primary sulphamide moiety have also been proved to possess a high CA inhibition activity 1,11,19,23 . As an example, compound JNJ-26990990 (2) (see Figure 1), which presents excellent anticonvulsant activity and can be potentially used in the treatment of multiple forms of epilepsy, is also a nanomolar inhibitor of several CA isoforms 24,25 .…”

How many carbonic anhydrase inhibition mechanisms exist?

“…Gavernet et al 154 explored N,N 0 -disubstituted sulfamides of types 80-94 or the N,O-disubstituted sulfamate 95, which showed a broad range of inhibitory activity and selectivity: some aromatic sulfamides were active against hCA I, hCA II and/or hCA VII, while they were less active against hCA XII and XIV. On the other hand, several bulky sulfamides were selective hCA VII inhibitors 154 .…”

“…On the other hand, several bulky sulfamides were selective hCA VII inhibitors 154 . The inhibitory mechanism of these compounds is also unknown, but it is rather probable that their bulky substituents at the NHSO 2 X (X ¼ NH or O) fragment of the molecule impairs their binding to the metal ion Figure 14.…”

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…In addition, a range of secondary and tertiary sulfonamides has been investigated as CAIs recently, some of them showing effective and selective inhibition of several important isoforms [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date.…”

“…However, the inhibition mechanism with secondary and tertiary sulfonamides is unknown, as no X-ray crystal structures of such derivatives bound to the CA are available to date. Thus, the sulfonamides reported here incorporate in their molecule the urea fragment found in SLC-0111 and the secondary sulfonamide moiety present in sulfa drugs and several recently investigated CAIs [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] .…”