Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action

  • Bioorg Med Chem. 2015 Jul 1;23(13):3860-8. doi: 10.1016/j.bmc.2015.03.037.
Tian-Qi Mao  1 ,  Qiu-Qin He  2 ,  Zheng-Yong Wan  3 ,  Wen-Xue Chen  3 ,  Fen-Er Chen  4 ,  Gang-Feng Tang  3 ,  Erik De Clercq  5 ,  Dirk Daelemans  5 ,  Christophe Pannecouque  5
Affiliations
  • 1. 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.
  • 2. Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: [email protected].
  • 3. Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
  • 4. 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].
  • 5. Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
PMID: 25907370 DOI: 10.1016/j.bmc.2015.03.037
Abstract

A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a Quinolone 3-carboxylic acid moiety in the molecules.

Keywords
Anti-HIV; Diarylpyrimidine–quinolone hybrids; HIV-1 reverse transcriptase; Integrase.