Carbonic anhydrase inhibitors: Anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties

被引:134
作者
Masereel, B
Rolin, S
Abbate, F
Scozzafava, A
Supuran, CT
机构
[1] Univ Florence, Lab Inorgan & Bioinorgan, I-50121 Florence, Italy
[2] Uni Namur, FUNDP, Dept Pharm, B-5000 Namur, Belgium
[3] Univ Florence, CSGI, I-50121 Florence, Italy
关键词
D O I
10.1021/jm0109199
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of aromatic/heterocyclic sulfonamides incorporating valproyl moieties were prepared to design antiepileptic compounds possessing in their structure two moieties known to induce such a pharmacological activity: valproic acid, one of the most widely used antiepileptic drugs, and the sulfonamide residue included in acetazolamide and topiramate, two carbonic anhydrase inhibitors with antiepileptic properties. Some of these derivatives showed very high inhibitory potency against three carbonic anhydrase (CA) isozymes, such as CA I, CA II, and CA IV, involved in important physiological processes. Topiramate, a recently developed antiepileptic drug possessing a sulfamate moiety, also shares this property, although earlier literature data reported this compound to be a weak-moderate CA I, II, and IV inhibitor. The valproyl derivative of acetazolamide (5-valproylamido-1,3,4-thiadiazole-2-sulfonamide, 6M) was one of the best hCA I and hCA II inhibitor in the series and exhibited very strong anticonvulsant properties in an MES test in mice. In consequence, other 1,3,4-thiadiazolesulfonamide derivatives possessing potent CA inhibitory properties and substituted with different alkyl/ arylcarboxamido/sulfonamido/ureido moieties in the 5 position have been investigated for their anticonvulsant effects in the same animal model. It was observed that some lipophilic derivatives, such as 5-benzoylamido-, 5-toluenesulfonylamido-, 5-adamantylcarboxamido-, and 5-pivaloylamido-1,3,4-thiadiazole-2-sulfonamide, show promising in vivo anticonvulsant properties and that these compounds may be considered as interesting leads for developing anticonvulsant or selective cerebrovasodilator drugs.
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收藏
页码:312 / 320
页数:9
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