Synthesis and carbonic anhydrase I, II, VII, and IX inhibition studies with a series of benzo[d]thiazole-5- and 6-sulfonamides

Abstract

A series of benzo[d]thiazole-5- and 6-sulfonamides has been synthesized and investigated for the inhibition of several human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, using ethoxzolamide (EZA) as lead molecule. 2-Amino-substituted, 2-acylamino- and halogenated (bromo-and iodo-derivatives at the heterocyclic ring) compounds led to several interesting inhibitors against the cytosolic hCA I, II and VII, as well as the transmembrane, tumor-associated hCA IX isoforms. Several subnanomolar/low nanomolar, isoform-selective sulfonamide inhibitors targeting hCA II, VII and IX were detected. The sharp structure–activity relationship for CA inhibition with this small series of derivatives, with important changes of activity observed even after minor changes in the scaffold or at the 2-amino moiety, make this class of scarcely investigated sulfonamides of particular interest for further investigations.

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…The scaffold of the potent and isoform‐selective CA IX inhibitors of this type incorporates aromatic, heterocyclic, aliphatic, sugar, or combinations of such moieties, and is obviously highly important for the inhibitory activity, as it makes extensive interactions with the active site of the enzyme in the enzyme‐inhibitor complex (as shown by extensive X‐ray crystallographic studies) . Again, effective and isoform‐selective CA IX inhibitors were obtained from all these classes of derivatives mentioned here (examples will be disclosed shortly).…”

“…As mentioned above, the main problem with the drug design of CA IX inhibitors was to obtain compounds which should selectively inhibit CA IX without a significant inhibitory effect against the physiologically dominant, highly abundant isoforms CA I and II (and also other off‐target isoforms) . This goal seemed to be difficult to achieve initially, but several classes of sulfonamides and their isosteres (sulfamates, sulfamides), most of which were obtained using the tail approach, allowed to obtain compounds with these features . Only the most relevant studies will be mentioned here, as this class of CAIs is the most investigated one and a high number of drug design studies (>400) have been reported since 2003 .…”

“…All these studies allowed the detailed understanding of the factors governing activity and selectivity for inhibiting CA IX over other CA isoforms, and are summarized below: the zinc‐binding group of the sulfonamide, sulfamate, and sulfamide is not highly influential for obtaining potent and CA IX‐selective inhibitors. In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides The scaffold of the potent and isoform‐selective CA IX inhibitors of this type incorporates aromatic,…”

“…In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides The scaffold of the potent and isoform‐selective CA IX inhibitors of this type incorporates aromatic, heterocyclic, aliphatic, sugar, or combinations of such moieties, and is obviously highly important for the inhibitory activity, as it makes extensive interactions with the active site of the enzyme in the enzyme‐inhibitor complex (as shown by extensive X‐ray crystallographic studies) . Again, effective and isoform‐selective CA IX inhibitors were obtained from all these classes of derivatives mentioned here (examples will be disclosed shortly). Probably the most important structural element influencing potency and selectivity is the tail that the zinc‐binding inhibitors incorporate, which has also been the topic mostly used for modulating the activity and selectivity profile of all these classes of CAIs.…”

“…the zinc‐binding group of the sulfonamide, sulfamate, and sulfamide is not highly influential for obtaining potent and CA IX‐selective inhibitors. In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides …”