期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 4, 页码 2083-2098出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01729
关键词
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资金
- National Natural Science Foundation of China (NSFC) [81273354]
- Key Project of NSFC for International Cooperation [81420108027]
- Young Scholars Program of Shandong University (YSPSDU) [2016WLJH32]
- Key research and development project of Shandong Province [2017CXGC1401]
- Major Project of Science and Technology of Shandong Province [2015ZDJS04001]
- Spanish Ministerio de Economia y Competitividad [SAF2017-88107-R, MDM-2017-0767]
- Generalitat de Catalunya [2017SGR1746]
- KU Leuven [GOA 10/014]
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.
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