Inhibition studies on a panel of human carbonic anhydrases withN1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails

Abstract

Being the primary sulfonamide among the most efficient zinc binding group (ZBG) to design inhibitors for the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1), herein, we propose an investigation on four physiologically important human (h) CAs (hCA I, II, IV, and IX) with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. The effect of the functionalisation of the sulfonamide group with five different substitution patterns, namely acetyl, pyridine, thiazole, pyrimidine, and carbamimidoyl, was evaluated in relation to the inhibition profile of the corresponding primary sulfonamide analogues. With most of these latter being nanomolar inhibitors of all four considered isoforms, a totally counterproductive effect on the inhibition potency can be ascribed to N1-functionalisations of the ZBG primary sulfonamide structure with pyridine, thiazole, and pyrimidine moieties. On the other hand, incorporation of less hindered groups, such as sulfonylacetamides and sulfonylguanidines, maintained a certain degree of activity dependent on the tailing moiety, with KIs spanning in the low micromolar range.

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

“…These compounds comprise several classes such as anions, thioureas, nitro compounds, uracil derivatives, phenols, sulfamates, and sulfonamides. Some of them selectively inhibit CA I/CA II or both over other isoforms of CAs 195–233 . It should be mentioned however, that although CA I is one of the most abundant isoforms in many tissues, its precise physiological role is still unknown 194 …”

“…However, the selectivity of these compounds was not up to mark over cancer‐associated isoform CA IX (Figure 5). 203 …”

Structure Activity Relationship of Key Heterocyclic Anti-Angiogenic Leads of Promising Potential in the Fight against Cancer

“…Sulfonamides significance stems from the fact that they constitute a significant class of drugs with various types of pharmacological effects including antitumor, anti-carbonic anhydrase, and diuretic activity [ 53 , 54 , 55 , 56 ]. There are many reports of a multitude of structurally novel heterocyclic sulfonamide derivatives that have been stated to display significant antitumor activity [ 57 , 58 ].…”

A class of carbonic anhydrase IX/XII – selective carboxylate inhibitors

“…Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay in order to allow for the formation of the E-I complex. The inhibition constants were obtained by nonlinear least-squares methods using PRISM 3 and the Cheng-Prusoff equation, as reported earlier [47][48][49][50] , and represent the mean from at least three different determinations. All CA isoforms were recombinant ones obtained in-house as reported earlier [51][52][53] .…”