开发新型二氢呋喃并[3,4-d]嘧啶衍生物作为 HIV-1 NNRTIs，以克服高度耐药突变株 F227L/V106A 和 K103N/Y181C。
Development of Novel Dihydrofuro[3,4-]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C.
机构信息
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
出版信息
J Med Chem. 2022 Feb 10;65(3):2458-2470. doi: 10.1021/acs.jmedchem.1c01885. Epub 2022 Jan 21.
Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds (EC = 5.79-28.3 nM) and (EC = 2.85-18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, and showed moderate RT enzyme inhibition (IC = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, and exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.
在这里，我们报告了二氢呋喃并[3,4-d]嘧啶衍生物作为一种有效的 HIV-1 非核苷逆转录酶抑制剂（NNRTIs）的设计、合成、构效关系研究、抗病毒活性、酶抑制和可药性评价。化合物（EC = 5.79-28.3 nM）和（EC = 2.85-18.0 nM）对一系列 HIV-1 耐药株表现出优异的活性。特别是对于突变体 F227L/V106A 和 K103N/Y181C，与依曲韦林和利匹韦林相比，这两种化合物的活性均显著提高。此外，化合物（EC = 0.14-0.15 μM）对 RT 酶有中等抑制作用，表明其为 HIV-1 NNRTIs。此外，化合物（EC = 0.14-0.15 μM）对 RT 酶有中等抑制作用，表明其为 HIV-1 NNRTIs。此外，化合物 和 表现出良好的药代动力学和安全性特性，使它们成为进一步开发的优秀先导化合物。
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