Pyrimidine sulfonylacetanilides with improved potency against key mutant viruses of HIV-1 by specific targeting of a highly conserved residue

  • Eur J Med Chem. 2015 Sep 18:102:215-22. doi: 10.1016/j.ejmech.2015.08.007.
Zheng-Yong Wan  1 ,  Jin Yao  1 ,  Tian-Qi Mao  2 ,  Xin-Long Wang  1 ,  Hai-Feng Wang  1 ,  Wen-Xue Chen  1 ,  Hong Yin  3 ,  Fen-Er Chen  4 ,  Erik De Clercq  5 ,  Dirk Daelemans  5 ,  Christophe Pannecouque  5
Affiliations
  • 1. Department of Chemistry, Fudan University, Shanghai 200433, PR China.
  • 2. Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China.
  • 3. Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: [email protected].
  • 4. Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China. Electronic address: [email protected].
  • 5. Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
PMID: 26276435 DOI: 10.1016/j.ejmech.2015.08.007
Abstract

Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the Reverse Transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.

Keywords
Antiviral agent; Biological activity; Highly conserved residue; Molecular hybridization; Molecular simulation.