A Class of Sulfonamides with Strong Inhibitory Action against the α‑Carbonic Anhydrase from Trypanosoma cruzi

• Published in: Journal of medicinal chemistry 2013-07, Vol.56 (14), p.5773-5781
• Main Authors: Güzel-Akdemir, Özlen, Akdemir, Atilla, Pan, Peiwen, Vermelho, Alane B, Parkkila, Seppo, Scozzafava, Andrea, Capasso, Clemente, Supuran, Claudiu T
• Format: Article
• Language: English
• Subjects: Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - pharmacology; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - pharmacology; Humans; Models, Molecular; Molecular Docking Simulation; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400418p

Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an α-carbonic anhydrase (CA, EC 4.2.1.1) possessing high catalytic activity (TcCA) which was recently characterized (Pan et al. J. Med. Chem. 2013, 56, 1761–1771). A new class of sulfonamides possessing low nanomolar/subnanomolar TcCA inhibitory activity is described here. Aromatic/heterocyclic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with K Is in the range of 0.5–12.5 nM, being less effective against the human off-target isoforms hCA I and II. A homology model of TcCA helped us to rationalize the excellent inhibition profile of these compounds against the protozoan enzyme, a putative new antitrypanosoma drug target. These compounds were ineffective antitrypanosomal agents in vivo due to penetrability problems of these highly polar molecules that possess sulfonamide moieties.