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新型 HIV-1 NNRTIs 的设计与合成：具有双环核心和改善的物理化学性质。

Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.

机构信息

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, Prague 6 160 00, Czech Republic.

Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 128 43, Czech Republic.

出版信息

J Med Chem. 2023 Feb 9;66(3):1761-1777. doi: 10.1021/acs.jmedchem.2c01574. Epub 2023 Jan 18.

DOI:10.1021/acs.jmedchem.2c01574
PMID:36652602
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10017027/
Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds , , and carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds , , and to the reverse transcriptase were studied by X-ray crystallography.

摘要

非核苷类逆转录酶抑制剂（NNRTIs）是当前治疗人类免疫缺陷病毒 1 型（HIV-1）感染方案的基石。然而，NNRTIs 通常水溶性低，而且容易出现耐药病毒株。在本工作中，设计并制备了新型的双环 NNRTIs，它们衍生自依曲韦林（ETV）和利匹韦林（RPV），具有修饰的嘌呤、四氢喋呤和嘧啶二氮杂䓬核心。带有丙烯腈部分的化合物 、 和 对野生型（WT）病毒显示出个位数纳摩尔级的活性（EC = 2.5、2.7 和 3.0 nM，分别），对 HXB2（EC = 2.2-2.8 nM）和 K103N 和 Y181C 突变株的活性保留不变（倍变化，1.2-6.7×）。最重要的是，化合物 与 ETV 和 RPV 相比，磷酸盐缓冲盐水的溶解度显著提高（10.4 μM）（≪1 μM）。此外，通过 X 射线晶体学研究了化合物 、 和 与逆转录酶的结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/498198fc8164/jm2c01574_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/72ce9a331caf/jm2c01574_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/344bd896eea0/jm2c01574_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/297994db9709/jm2c01574_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/2c4f4bd82c9e/jm2c01574_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/46ae1b0c2d01/jm2c01574_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/7e397c5a9029/jm2c01574_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/d1d78bfa923a/jm2c01574_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/a501da229329/jm2c01574_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/e92b60041bdd/jm2c01574_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/e2becbbd6331/jm2c01574_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/498198fc8164/jm2c01574_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/72ce9a331caf/jm2c01574_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/344bd896eea0/jm2c01574_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/297994db9709/jm2c01574_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/2c4f4bd82c9e/jm2c01574_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/46ae1b0c2d01/jm2c01574_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/7e397c5a9029/jm2c01574_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/d1d78bfa923a/jm2c01574_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/a501da229329/jm2c01574_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/e92b60041bdd/jm2c01574_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/e2becbbd6331/jm2c01574_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5780/10017027/498198fc8164/jm2c01574_0005.jpg

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