Development of Novel Dihydrofuro[3,4-d]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C
Development of Novel Dihydrofuro[3,4-d]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C
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DOI：
10.1021/acs.jmedchem.1c01885
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发表时间：
2022-01-21
影响因子：
7.3
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
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作者：
Kang, Dongwei;Sun, Yanying;Liu, Xinyong
在此，我们报告了二氢呋喃并[3,4-d]嘧啶衍生物作为一类有效的 HIV-1 非核苷逆转录酶抑制剂 (NNRTI) 的设计、合成、构效关系研究、抗病毒活性、酶抑制和成药性评估。化合物14b (EC50 = 5.79-28.3 nM) 和16c (EC50 = 2.85-18.0 nM) 对一组HIV-1 抗性菌株表现出优异的效力。特别是，对于换形体突变F227L/V106A和K103N/Y181C，与依曲韦林和利匹韦林相比，两种化合物均表现出显着改善的活性。此外，14b和16c显示出中等的RT酶抑制作用（IC50=0.14-0.15μM），这表明它们起到HIV-1 NNRTI的作用。此外，14b 和 16c 表现出良好的药代动力学和安全特性，使其成为进一步开发的绝佳先导。
Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b (EC50 = 5.79-28.3 nM) and 16c (EC50 = 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, 14b and 16c showed moderate RT enzyme inhibition (IC50 = 0.14-0.15 mu M), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.