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

被引：55

作者：

Guzel-Akdemir, Ozlen ^{[1
]}

Akdemir, Atilla ^{[2
]}

Pan, Peiwen ^{[3
,4
,5
]}

Vermelho, Alane B. ^{[6
]}

Parkkila, Seppo ^{[3
,4
,5
]}

Scozzafava, Andrea ^{[7
]}

Capasso, Clemente ^{[8
]}

Supuran, Claudiu T. ^{[7
,9
]}

机构：

[1] Istanbul Univ, Fac Pharm, Dept Pharmaceut Chem, TR-34116 Istanbul, Turkey

[2] Bezmialem Vakif Univ, Fac Pharm, Dept Pharmacol, Istanbul, Turkey

[3] Univ Tampere, Sch Med, Fimlab Ltd, Inst Biomed Technol, Tampere 33520, Finland

[4] Univ Tampere, BioMediTech, Tampere 33520, Finland

[5] Tampere Univ Hosp, Tampere 33520, Finland

[6] Univ Fed Rio de Janeiro UFRJ, Lab Proteases Microrganismos, Inst Microbiol Paulo de Goes, CCS,Ilha Fundao, Rio De Janeiro, RJ, Brazil

[7] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy

[8] CNR, Ist Biochim Prot, I-80131 Naples, Italy

[9] Univ Florence, NEUROFARBA Dept, Sez Sci Farmaceut, I-50019 Florence, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 14期

基金：

芬兰科学院;

关键词：

DRUG DISCOVERY; PATENT; CAH-4B;

D O I：

10.1021/jm400418p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an alpha-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/heterocydic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with K(I)s 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.

引用

页码：5773 / 5781

页数：9

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