Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs
- Bioorg Med Chem. 2014 Jan 1;22(1):633-42. doi: 10.1016/j.bmc.2013.10.033.
- 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Ji'nan, Shandong, PR China.
- 2. Institute of Pharmacology, School of Medicine, Shandong University, 44, West Culture Road, 250012 Ji'nan, Shandong, PR China.
- 3. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
- 4. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: [email protected].
A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (Reverse Transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.