Design,synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs |
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Authors: | Diwakar Rai Wenmin Chen Ye Tian Xuwang Chen Peng Zhan Erik De Clercq Christophe Pannecouque Jan Balzarini Xinyong Liu |
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Affiliation: | 1. Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Educational Ministry of China), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China;2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium |
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Abstract: | A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a–8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC50 = 0.05–35 μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC50 = 0.07 μM, CC50 >347 μM, SI >4870; EC50 = 0.05 μM, CC50 = 42 μM, SI = 777, respectively), comparable to that of the marked drug nevirapine (EC50 = 0.113 μM, CC50 >15 μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties. |
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