Vullo Daniela, Del Prete Sonia, Fisher Gillian M, Andrews Katherine T, Poulsen Sally-Ann, Capasso Clemente, Supuran Claudiu T
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
Istituto di Bioscienze e Biorisorse (IBBR)-CNR, Via P. Castellino 111, 80131 Napoli, Italy.
Bioorg Med Chem. 2015 Feb 1;23(3):526-31. doi: 10.1016/j.bmc.2014.12.009. Epub 2014 Dec 11.
The η-carbonic anhydrases (CAs, EC 4.2.1.1) were recently discovered as the sixth genetic class of this metalloenzyme superfamily, and are so far known only in protozoa, including various Plasmodium species, the causative agents of malaria. We report here an inhibition study of the η-CA from Plasmodium falciparum (PfCA) against a panel of sulfonamides and one sulfamate compound, some of which are clinically used. The strongest inhibitors identified were ethoxzolamide and sulthiame, with KIs of 131-132 nM, followed by acetazolamide, methazolamide and hydrochlorothiazide (KIs of 153-198 nM). Brinzolamide, topiramate, zonisamide, indisulam, valdecoxib and celecoxib also showed significant inhibitory action against PfCA, with KIs ranging from 217 to 308 nM. An interesting observation was that the more efficient PfCA inhibitors are representative of several scaffolds and chemical classes, including benzene sulfonamides, monocyclic/bicyclic heterocyclic sulfonamides and compounds with a more complex scaffold (i.e., the sugar sulfamate derivative, topiramate, and the coxibs, celecoxib and valdecoxib). A comprehensive inhibition study of small molecules for η-CAs is needed as a first step towards assessing PfCA as a druggable target. The present work identifies the first known η-CA inhibitors and provides a platform for the development of next generation novel PfCA inhibitors.
η-碳酸酐酶（CAs，EC 4.2.1.1）最近被发现是这种金属酶超家族的第六个基因类别，目前仅在原生动物中发现，包括各种疟原虫物种，即疟疾的病原体。我们在此报告了对恶性疟原虫的η-CA（PfCA）针对一组磺胺类药物和一种氨基磺酸盐化合物的抑制研究，其中一些在临床上有应用。鉴定出的最强抑制剂是乙氧唑胺和舒噻美，抑制常数（KIs）为131 - 132 nM，其次是乙酰唑胺、甲醋唑胺和氢氯噻嗪（KIs为153 - 198 nM）。布林佐胺、托吡酯、唑尼沙胺、茚地那韦、伐地昔布和塞来昔布对PfCA也显示出显著的抑制作用，KIs范围为217至308 nM。一个有趣的观察结果是，更有效的PfCA抑制剂代表了几种支架和化学类别，包括苯磺酰胺、单环/双环杂环磺酰胺以及具有更复杂支架的化合物（即糖氨基磺酸盐衍生物托吡酯以及昔布类药物塞来昔布和伐地昔布）。作为将PfCA评估为可成药靶点的第一步，需要对小分子对η-CAs进行全面的抑制研究。目前的工作鉴定出了首批已知的η-CA抑制剂，并为开发下一代新型PfCA抑制剂提供了一个平台。
