2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase.
2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase.
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DOI：
10.1016/j.ejmech.2014.07.072
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发表时间：
2014-10
影响因子：
6.7
通讯作者：
Zhongliang Xu;Mingyu Ba;Hua Zhou;Ying-li Cao;Chaojun Tang;Ying Yang;Ricai He;Yu-mei Liang;
中科院分区：
文献类型：
--
作者：
Zhongliang Xu;Mingyu Ba;Hua Zhou;Ying-li Cao;Chaojun Tang;Ying Yang;Ricai He;Yu-mei Liang;
设计并合成了一类新型的2，4，5-三取代噻唑衍生物（TSTs）作为HIV-1非核苷类逆转录酶抑制剂（NNRTIs）。在合成的38个目标化合物中，30个TST在亚微摩尔浓度（0.046 - 9.59 μM）下对野生型HIV-1中的HIV-1复制表现出有效的抑制作用。化合物21、23和24也对7个NNRTI耐药HIV-1株进行了测试，并且都表现出抑制作用，IC 50的倍数变化范围为2.6 - 111，其优于奈韦拉平（15.6-371倍）。对接模拟结果揭示了化合物24的合理结合机制，三维定量构效关系（3-DQSAR）研究进一步阐明了TST的构效关系。结果表明TSTs作为一类具有抗病毒疗效和良好耐药性的新型NNRTIs具有巨大的潜力。
Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds21,23and24were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold–371-fold). Docking simulations of compound24revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure–activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.