Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases

Abstract

A diverse set of mono- and bis-sulfonamide was obtained via a direct, chemoselective sulfochlorination of readily available yet hitherto unexplored N-arylpyrazole template. Biochemical profiling of compounds thus obtained against a panel of human carbonic anhydrases ( h CA I, h CA II, h CA IV and h CA VII) revealed a number of leads that are promising from the isoform selectivity prospective and exhibit potent inhibition profile (from nanomolar to micromolar range). The observed SAR trends have been rationalized by in silico docking of selected compounds into the active site of all four isoforms. The results reported in this paper clearly attest to the power of direct sulfochlorination as the means to create carbonic anhydrase focused sets in order to identify isoform selective inhibitors of closely related enzymes.

Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors

“…The inhibition constants were obtained by non-linear least-squares methods using the Cheng-Prusoff equation, as reported earlier 20–24 , and represent the mean from at least three different determinations. All CA isozymes used here were recombinant proteins obtained as reported earlier by our group 10 c, 25 , 26 .…”

“…Despite that, all these five membrane-bound isoforms are commonly termed as extracellular CAs due to having their active sites outside the cell. Many sulfonamide-based drugs (Figure 2) such as acetazolamide (AAZ), methazolamide, ethoxzolamide, dorzolamide, brinzolamide, dichlorophenamide, and celecoxib are used clinically for many years as diuretics, anti-epileptics, anti-glaucoma, or as anti-tumor agents 9 , 10 .…”

Antiproliferative Activity of New Pyrazole-4-sulfonamide Derivatives: Synthesis and Biological Evaluation

“…The lower organic layer was separated, dried over sodium sulfate, and evaporated under vacuum to obtain 3,5-dimethyl-1 H -pyrazolesulfonyl chloride and 1,3,5-trimethyl-1 H -pyrazolesulfonyl chloride (Scheme ). − …”

Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery

“…In the recent study performed by Krasavin M. et al a novel series of substituted 1,2,4-oxadiazole-arylsulfonamides has been discovered as selective CA inhibitors with potential application in the cancer therapies [73,74]. An extensive research (conducted by the same research group) exploring various substituted heterocyclic compounds (including 1,3-oxazole, isoxazole, imidazoline and pyrazole) with sulfonamide moiety indicated that 1,2,4-oxadiazol-5-yl-benzene sulfonamides were able to demonstrate extremely high biological activity and selectivity [87][88][89][90]. Inhibitory potency of synthesized compounds was measured with the use of CO 2 hydration stopped-flow biochemical assay against two cytosolic Human Carbonic Anhydrases (hCA I and II) and two membrane-bound cancer related (hCA IX and XII) CA.…”