Trapani G, Franco M, Latrofa A, Carotti A, Cellamare S, Serra M, Ghiani C A, Tuligi G, Biggio G, Liso G
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Italy.
J Pharm Pharmacol. 1996 Aug;48(8):834-40. doi: 10.1111/j.2042-7158.1996.tb03984.x.
To identify more potent anticonvulsant agents and to gain insights into the structural properties determining the potency of a new class of anticonvulsants, some 3a-substituted tetrahydropyrrolo[2,1-b]benzothiazol-1-ones (1a-d) and the thiazole and oxazole analogues (2a-c and 3a-c, respectively) have been synthesized and tested for anticonvulsant activity against isoniazid-induced seizures in rodents. The most active compound, 2a, with a median effective dose (ED50, i.p.) of 24.3 mg kg-1 and 15.9 mg kg-1 in mice and in rats, respectively, was more extensively investigated and found to strengthen the effects of diazepam. No clear correlation was observed between the anticonvulsant activity and molecular lipophilicity descriptors of compounds 1-3. Structural similarity between the antiepileptic drug phenobarbital and compounds 1-3 was evidenced by molecular modelling studies and used to derive preliminary structure-activity relationships. The results demonstrate that 2a is an attractive candidate as an anticonvulsant agent worthy of further study and may help the design of other anticonvulsant drugs.
为了鉴定更有效的抗惊厥药物，并深入了解决定一类新型抗惊厥药效力的结构特性，已合成了一些3a-取代的四氢吡咯并[2,1-b]苯并噻唑-1-酮（1a-d）以及噻唑和恶唑类似物（分别为2a-c和3a-c），并测试了它们对啮齿动物异烟肼诱导的惊厥的抗惊厥活性。活性最强的化合物2a，在小鼠和大鼠中的半数有效剂量（ED50，腹腔注射）分别为24.3 mg kg-1和15.9 mg kg-1，对其进行了更广泛的研究，发现它能增强地西泮的作用。在化合物1-3的抗惊厥活性与分子亲脂性描述符之间未观察到明显的相关性。通过分子模拟研究证明了抗癫痫药物苯巴比妥与化合物1-3之间的结构相似性，并用于推导初步的构效关系。结果表明，2a作为一种值得进一步研究的抗惊厥药物是一个有吸引力的候选物，可能有助于设计其他抗惊厥药物。
