以高活性的2-甲氧/乙氧羰基-4-(4-氟苯基)-1,5-苯并硫氮杂 A和B为模型化合物,设计合成了11个含氟杂衍生物3a~3k,考察了它们对白色念珠菌和新生隐球菌的抑菌活性。研究结果表明,2-甲氧/乙氧羰基-4-(2-氟苯基)/(3-氟苯基)/(2,4-二氟苯基)-1,5-苯并硫氮杂3a,3b,3d~3f对新生隐球菌有很强的抑菌活性,3c的活性中等,而7位氯代杂3g~3k基本无活性；上述杂对白色念珠菌均无活性。在此基础上,进一步测试了高活性杂3a,3b,3d~3f对新生隐球菌的抑菌浓度梯度、最小抑菌浓度( MIC)和最小杀菌浓度(MFC),发现其MIC和MFC均远低于对照药氟康唑。为了考察杂3a~3f的药效基团,又设计合成了4类杂衍生物4a~4f,5a~5f,6a~6f和7a~7c,通过对其抑菌活性的评价,发现分子中2-甲氧/乙氧羰基和亚胺官能团对杂3a~3f的抑真菌(新生隐球菌)活性起关键作用,硫原子被氧原子或氮原子代替后原杂的活性降低。%Using A and B as the prototypical structure, eleven 1,5-benzothiazepine derivatives 3a—3k were synthesized and evaluated for their antifungal activity against C. albicans and C. neoformans via the disk diffu-sion method. The results showed that benzothiazepines 3a, 3b and 3d—3f had good antifungal activity against C. neoformans, compound 3c had moderate activity, and 7-chloro-substituted analogues 3g—3k were weakly active or inactive. In addition, all of the benzothiazepines 3a—3k were almost inactive against C. albicans. Furthermore, compounds 3a, 3b and 3d—3f, which had good antifungal activities, were subjected to further pharmacological evaluation, including determining the dose dependence of the antifungal activity, minimum inhibitory concentration ( MIC ) and minimum fungicidal concentration ( MFC ) against C. neoformans. The results showed that the MIC and MFC values for above compounds were much lower than those of fluconazole. In order to examine the structural features responsible for the antifungal activity of compounds 3a—3f, four series of 1,5-benzothiazepine derivatives 4a—4f, 5a—5f, 6a—6f and 7a—7c were synthesized and screened for their antifungal activity. The results demonstrated that the methoxycarbonyl/ethoxycarbonyl group at the 2 position and imine moiety on the seven-membered ring of benzothiazepines 3 a—3 f was critical to their biologi-cal activity. The results also indicated that replacement of sulfur atom in the molecules with nitrogen or oxygen atom led to decrease in activity of this series of compounds.
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