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
  • 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: [email protected].
  • 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: [email protected].
  • 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.