嘧啶砜基乙酰胺类作为有效的 HIV-1 逆转录酶非核苷抑制剂的药效团融合设计。
Pharmacophore-fusing design of pyrimidine sulfonylacetanilides as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
机构信息
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, People's Republic of China.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
出版信息
Bioorg Chem. 2020 Mar;96:103595. doi: 10.1016/j.bioorg.2020.103595. Epub 2020 Jan 22.
Twenty-seven derivatives (40-66) were generated by pharmacophore fusing of sulfonylacetanilide-diarylpyrimidine (1) with rilpivirine or biphenyl-diarylpyrimidines. They displayed up to single-digit nanomolar activity against wild-type (WT) virus and various drug-resistant mutant strains in HIV-1-infected MT-4 cells, thereby targeting the reverse transcriptase (RT) enzyme. Compound 51 displayed exceptionally potent activity against WT virus (EC = 6 nM) and several mutant strains (L100I, EC = 8 nM, K103N, EC = 6 nM, Y181C, EC = 26 nM, Y188L, EC = 122 nM, E138K, EC = 26 nM). The structure-activity relationships of the newly obtained pyrimidine sulfonylacetanilides were also elucidated. Molecular docking analysis explained the activity and provided a structural insight for follow-up research.
二十七个衍生物（40-66）通过磺酰基乙酰胺-二芳基嘧啶（1）与利匹韦林或联苯二芳基嘧啶的药效团融合生成。它们在感染 HIV-1 的 MT-4 细胞中对野生型（WT）病毒和各种耐药突变株显示出高达个位数纳摩尔的活性，从而靶向逆转录酶（RT）酶。化合物 51 对 WT 病毒（EC=6 nM）和几种突变株（L100I，EC=8 nM，K103N，EC=6 nM，Y181C，EC=26 nM，Y188L，EC=122 nM，E138K，EC=26 nM）显示出异常强的活性。新获得的嘧啶磺酰基乙酰胺的结构-活性关系也得到了阐明。分子对接分析解释了活性，并为后续研究提供了结构见解。
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