Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles.
Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles.
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DOI：
10.1039/c2ob25904d
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发表时间：
2012-08
影响因子：
3.2
通讯作者：
T. Mizuhara;S. Oishi;H. Ohno;Kazuya Shimura;M. Matsuoka;N. Fujii
中科院分区：
文献类型：
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作者：
T. Mizuhara;S. Oishi;H. Ohno;Kazuya Shimura;M. Matsuoka;N. Fujii
3，4-二氢-2H，6 H-嘧啶并[1，2-c][1，3]苯并噻嗪-6-亚胺（PD 404182）是一种具有抗多种病毒活性的杀病毒杂环化合物，包括HCV、HIV和猿猴免疫缺陷病毒。利用我们开发的用于合成嘧啶并[1，2-c][1，3]苯并噻嗪-6-亚胺及其相关三环衍生物的简便合成方法，研究了PD 404182的中心1，3-噻嗪-2-亚胺核、苯部分和环脒部分的平行结构优化。用5-6-6或6-6-5衍生物取代6-6-6嘧啶并[1，2-c][1，3]苯并噻嗪-6-亚胺骨架导致抗HIV活性的显著损失，并且在9-或10-位引入疏水基团改善了效力。此外，我们证明了PD 404182衍生物在病毒感染的早期阶段发挥抗HIV作用。
3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is a virucidal heterocyclic compound active against various viruses, including HCV, HIV, and simian immunodeficiency virus. Using facile synthetic approaches that we developed for the synthesis of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic derivatives, the parallel structural optimizations of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 were investigated. Replacement of the 6-6-6 pyrimido[1,2-c][1,3]benzothiazin-6-imine framework with 5-6-6 or 6-6-5 derivatives led to a significant loss of anti-HIV activity, and introduction of a hydrophobic group at the 9- or 10-positions improved the potency. In addition, we demonstrated that the PD 404182 derivative exerts anti-HIV effects at an early stage of viral infection.