标题:Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles
作者:Huang, Boshi; Chen, Wenmin; Zhao, Tong; Li, Zhenyu; Jiang, Xiangyi; Ginex, Tiziana; Vilchez, David; Luque, Francisco Javier; Kang, Don 更多
作者机构:[Huang, Boshi; Chen, Wenmin; Zhao, Tong; Jiang, Xiangyi; Kang, Dongwei; Gao, Ping; Zhang, Jian; Tian, Ye; Zhan, Peng; Liu, Xinyong] Shandong Univ, Sch 更多
通讯作者:Zhan, P;Liu, XY;Pannecouque, C
通讯作者地址:[Zhan, P; Liu, XY]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples 更多
来源:JOURNAL OF MEDICINAL CHEMISTRY
出版年:2019
卷:62
期:4
页码:2083-2098
DOI:10.1021/acs.jmedchem.8b01729
摘要:Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 mu M, EC50(E138K) = 0.0075 mu M) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 >= 173 mu M). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/ subacute toxicities at doses of 2000 mg.kg(-1)/50 mg-kg(-1) in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.
收录类别:SCOPUS;SCIE
资源类型:期刊论文
原文链接:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062364408&doi=10.1021%2facs.jmedchem.8b01729&partnerID=40&md5=bab9f7cfdf38ef34c21724cf4f0356b6
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