双环芳基氨基嗪作为HIV-1逆转录酶强效抑制剂的发现与晶体学研究
Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase.
作者信息
Lee Won-Gil, Frey Kathleen M, Gallardo-Macias Ricardo, Spasov Krasimir A, Chan Albert H, Anderson Karen S, Jorgensen William L
机构信息
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
出版信息
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4824-4827. doi: 10.1016/j.bmcl.2015.06.074. Epub 2015 Jul 9.
Abstract
Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
摘要
据报道，HIV-1逆转录酶（HIV-RT）的非核苷抑制剂在嘧啶或1,3,5-三嗪核心上带有7-中氮茚基氨基或2-萘基氨基取代基。最有效的化合物对野生型HIV-1以及携带Tyr181Cys和Lys103Asn/Tyr181Cys耐药突变的变体显示出低于10纳摩尔的活性。这些化合物还具有良好的水溶性。两种复合物的晶体结构增强了对构效关系数据的分析。
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