Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: Optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches
Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: Optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches
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带有桥头氮的稠合杂环作为有效的 HIV-1 NNRTI。
DOI：
10.1016/j.ejmech.2015.01.042
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发表时间：
2015-03-06
影响因子：
6.7
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
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作者：
Huang, Boshi;Li, Cuicui;Liu, Xinyong
为了开发新型HIV-1非核苷类逆转录酶（RT）抑制剂（NNRTI），我们设计、合成了新型哌啶连接的[1，2，4]三唑并[1，5-a]嘧啶衍生物，并在MT-4细胞培养中评价了其抗病毒活性。生物学结果表明，所有标题化合物对野生型（wt）HIV-1株（IIIB）显示出中等至优异的活性，在基于细胞的测定中，EC 50值范围为8.1 nM至2284 nM。其中，最有希望的类似物7 d对wt HIV-1具有8.1 nM的EC 50值，其比参比药物DDI、3 TC、NVP和DLV强得多。此外，7 d对双突变HIV-1株（K103 N + Y181 C）表现出较弱的活性，在RT抑制试验中比NW更有效。此外，还对7 d的一些理化性质如log P、水溶性等进行了测定和计算，并对其构效关系（SAR）进行了分析。此外，通过分子模拟研究合理化了活性化合物7 d的结合模式。(C)2015年Elsevier Masson SAS。All rights reserved.
In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NW in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies. (C) 2015 Elsevier Masson SAS. All rights reserved.