Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents |
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| Authors: | Jian Tang Keduo Qian Bei-Na Zhang Ying Chen Peng Xia Donglei Yu Yi Xia Zheng-Yu Yang Chin-Ho Chen Susan L Morris-Natschke Kuo-Hsiung Lee |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China;2. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;3. Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA |
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| Abstract: | Thirteen novel seco-DCK analogs (4–16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC50: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate. |
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