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
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.