Design, synthesis and anti-HIV evaluation of 5-alkyl-6-(benzo[d][1,3] dioxol-5-alkyl)-2-mercaptopyrimidin-4(3H)-ones as potent HIV-1 NNRTIs
Design, synthesis and anti-HIV evaluation of 5-alkyl-6-(benzo[d][1,3] dioxol-5-alkyl)-2-mercaptopyrimidin-4(3H)-ones as potent HIV-1 NNRTIs
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5-烷基-6-(苯并[d][1,3]二氧杂环己烷-5-烷基)-2-巯基嘧啶-4(3H)-酮作为有效的 HIV-1 NNRTI 的设计、合成和抗 HIV 评估
DOI：
10.1016/j.bioorg.2020.104041
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发表时间：
2020-09-01
影响因子：
5.1
通讯作者：
Xiao, Wei-Lie
中科院分区：
文献类型：
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作者：
Li, Yi-Ming;Luo, Rong-Hua;Xiao, Wei-Lie
为了发现和开发新的HIV-1非核苷类逆转录酶抑制剂，合成了一系列5-烷基-6-（苯并[d][1，3]间二氧杂环戊烯-5-基烷基）-2-巯基嘧啶-4（3 H）-酮类化合物，并对其进行了体外抗HIV-1细胞毒活性筛选。我们合成的大多数化合物显示出对野生型HIV-1株（IIIB）的高活性，而IC 50值在0.06-12.95 μ M的范围内。其中，最具活性的HIV-1抑制剂是化合物6-（苯并[d][1，3]间二氧杂环戊烯-5-基甲基）-5-乙基-2-（（2-（4-羟基苯基）-2-氧代乙基）硫代）嘧啶-4（3 H）-酮（5 b），其表现出类似的HIV-1抑制效力与奈韦拉平（IC 50 = 0.04 μ M，CC 50 = 200 μ M）相比，大多数化合物显示亚微摩尔IC 50值，表明它们是特异性RT抑制剂。化合物5 b、6-（苯并[d] [1，3]间二氧杂环戊烯-5-基）-5-乙基-2-（（2-（4-羟基苯基）2-氧代乙基）硫代）嘧啶-4（3 H）-酮（5c）和4-（2-（（4-（苯并[d][1，3]间二氧杂环戊烯-5-基甲基）-5-乙基-6-氧代-1，6-二氢嘧啶-2-基）硫代）乙酰基）苯基苯并[d][1，3]间二氧杂环戊烯-5-甲酸酯（5 r）被选择用于进一步研究。结果发现，它们对外周血单核细胞（PBMC）的毒性很小，对HIV-1蛋白酶抑制剂耐药株、融合抑制剂耐药株、核苷类逆转录酶抑制剂耐药株以及临床分离株的复制均具有良好的抑制作用。此外，化合物5 b和5c对HIV-1 RT RNA依赖的DNA聚合活性和DNA依赖的DNA聚合活性均有抑制作用，而化合物5 r仅对HIV DNA依赖的DNA聚合活性有抑制作用，这与经典的逆转录酶抑制剂不同。本研究为这些新化合物的构效关系和模型研究提供了初步的思路，为今后的分子优化提供了有价值的途径。
In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC50 values are in the range of 0.06-12.95 mu M. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3] dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b), which exhibited similar HIV-1 inhibitory potency (IC50 = 0.06 mu M, CC50 = 96.23 mu M) compared with nevirapine (IC50 = 0.04 mu M, CC50 200 mu M) and most of compounds exhibited submicromolar IC50 values indicating they were specific RT inhibitors. The compounds 5b, 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization.