期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 40, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116195
关键词
Drug design; HIV-1; DAPYs; NNRTIs; Drug resistance; Antiviral
资金
- National Natural Science Foundation of China (NSFC) [81973181]
- Key Project of NSFC for International Cooperation [81420108027]
- Key Research and Development Project of Shandong Province [2017CXGC1401, 2019JZZY021011]
- Foreign Cultural and Educational Experts Project [GXL20200015001]
- program for Outstanding PhD candidate of Shandong University
Novel diarylpyrimidine derivatives designed and synthesized in the study demonstrated strong anti-HIV activity, with compounds IVB-5-4 and IVB-5-8 showing superior activity against HIV-1(IIIB). These compounds not only exhibited potent inhibition against wide-type HIV-1 strain, but also showed low nanomole activity against some mutant strains.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV1. As a continuation of our efforts to discover and develop me-better drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (IIIB) with EC50 values in the range of 2.5 nM similar to 0.93 mu M. Among them, compounds IVB-5-4 and IVB-5-8 were the most potent ones which showed anti-HIV-1(IIIB) activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What's more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5-4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC50 values indicating that this series compounds are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.
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