A Class of Sulfonamides with Strong Inhibitory Action against the 伪-Carbonic Anhydrase from Trypanosoma cruzi

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• 作者：脰zlen G眉zel-Akdemir ; Atilla Akdemir ; Peiwen Pan ; Alane B. Vermelho ; Seppo Parkkila ; Andrea Scozzafava ; Clemente Capasso ; Claudiu T. Supuran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5773-5781
• 全文大小：386K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an 伪-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鈥?771). 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鈥?2.5 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.