Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors
Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors
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DOI：
10.1016/j.bmc.2004.05.037
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发表时间：
2004-08-15
影响因子：
3.5
通讯作者：
Neamati, N
中科院分区：
文献类型：
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作者：
Aiello, F;Brizzi, A;Neamati, N
噻唑并氮类药物是人类免疫缺陷病毒1型整合酶(HIV-1 IN)抑制剂(J Med.陈特。1999、42、3334)。在此之前，我们在基于细胞的检测中发现了两种具有抗病毒活性的噻唑并噻卓类药物。这些分子的结构优化需要设计易于合成的类似物。为了设计取代基数最少的类似分子，本文报道了10个新的类似物的合成。其中一个新化合物(1)表现出与参考化合物相似的效力，证实了硫杂环二酮与萘环体系的融合是分子适应IN活性中心的最佳组合。因此，用氧取代噻唑环中的硫似乎不会对效价产生很大影响。另一方面，在多环体系的第1位引入额外的甲基或从噻嗪转移到恶氮平骨架会降低效力。为了了解它们与IN活性中心的相互作用模式，我们将所有化合物对接到先前报道的IN的X射线晶体结构上。我们观察到化合物7-9占据了接近D64和Mg2+的区域，并被氨基酸残基K159、K156、N155、E152、D116、H67和T66包围。恶唑环7和8上的氧原子对镁离子有络合作用。这些结果表明，新的类似物可能与高度保守的残基相互作用，这些残基对IN的催化活性很重要。(C)2004爱思唯尔有限公司。保留所有权利。
Thiazolothiazepines are among the smallest and most constrained inhibitors of human immunodeficiency virus type-1 integrase (HIV-1 IN) inhibitors (J Med. Chent. 1999, 42, 3334). Previously, we identified two thiazolothiazepines lead IN inhibitors with antiviral activity in cell-based assays. Structural optimization of these molecules necessitated the design of easily synthesizable analogs. In order to design similar molecules with least number of substituent, herein we report the synthesis of 10 novel analogs. One of the new compounds (1) exhibited similar potency as the reference compounds, confirming that a thiazepinedione fused to a naphthalene ring system is the best combination for the molecule to accommodate into the IN active site. Thus, the replacement of sulfur in the thiazole ring with an oxygen does not seem considerably affect potency. On the other hand, the introduction of an extra methyl group at position 1 of the polycyclic system or the shift from a thiazepine to an oxazepine skeleton decreased potency. In order to understand their mode of interactions with IN active site, we docked all the compounds onto the previously reported X-ray crystal structure of IN. We observed that compounds 7-9 occupied an area close to D64 and Mg2+ and surrounded by amino acid residues K159, K156, N155 E152, D116, H67, and T66. The oxygen atom of the oxazolo ring of 7 and 8 could chelate Mg2+. These results indicate that the new analogs potentially interact with the highly conserved residues important for IN catalytic activities. (C) 2004 Elsevier Ltd. All rights reserved.