Abstract
A series of N-aryl-β-alanine derivatives and diazobenzenesulfonamides containing aliphatic rings were designed, synthesized, and their binding to carbonic anhydrases (CA) I, II, VI, VII, XII, and XIII was studied by the fluorescent thermal shift assay and isothermal titration calorimetry. The results showed that 4-substituted diazobenzenesulfonamides were more potent CA binders than N-aryl-β-alanine derivatives. Most of the N-aryl-β-alanine derivatives showed better affinity for CA II while diazobenzenesulfonamides possessed nanomolar affinities towards CA I isozyme. X-ray crystallographic structures showed the modes of binding of both compound groups.
Highlights
Since the discovery of the antibacterial activity of protonsil in 1932 [1], a wide array of aryl- and heteroarylsulfonamides exhibiting a variety of biological activities including antibacterial, antimicrobial, antifungal, anti-HIV, antihelmintic, anti-inflammatory, phytotoxic, cytotoxic, and radiosensitizing properties has been synthesized [2,3,4,5,6,7]
We report the synthesis of new N-aryl-β-alanine derivatives containing a primary sulfonamide moiety. We investigated these compounds as inhibitors of six carbonic anhydrase isoforms: carbonic anhydrases (CA) I, II, VI, VII, XII, and XIII
N-Substituted-β-alanine 3 [26] was obtained in the reaction of 1 with acrylic acid in aqueous solution in the presence of a catalytic amount of hydroquinone, whereas the reaction of 2 with acrylic acid in a mixture of toluene and acetic acid provided 3-[(4-{[bis(ethylthio)-methylene]sulfamoyl}phenyl) amino]propanoic acid (4)
Summary
Since the discovery of the antibacterial activity of protonsil in 1932 [1], a wide array of aryl- and heteroarylsulfonamides exhibiting a variety of biological activities including antibacterial, antimicrobial, antifungal, anti-HIV, antihelmintic, anti-inflammatory, phytotoxic, cytotoxic, and radiosensitizing properties has been synthesized [2,3,4,5,6,7]. Most of such compounds were secondary sulfonamides. The design of isoform-selective CA inhibitors could lead to drugs with fewer side effects compared to the currently used ones [13]
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