2. Academic Validation
  3. Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

  • Bioorg Med Chem. 2015 Aug 1;23(15):4248-4255. doi: 10.1016/j.bmc.2015.06.048.
Zheng-Yong Wan 1,  Yuan Tao 1,  Ya-Feng Wang 1,  Tian-Qi Mao 2,  Hong Yin 1,  Fen-Er Chen 3,  Hu-Ri Piao 4,  Erik De Clercq 5,  Dirk Daelemans 5,  Christophe Pannecouque 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
  • 2 Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China.
  • 3 Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.
  • 4 Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University, Yanji 133000, People's Republic of China. Electronic address: piaohuri@aliyun.com.
  • 5 Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
PMID: 26162497 DOI: 10.1016/j.bmc.2015.06.048
Abstract

A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.

Keywords

Antiviral agent; Biological activity; Etravirine; Molecular hybridization; VRX-480773.

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