Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors

  • Bioorg Med Chem. 2014 Apr 15;22(8):2535-41. doi: 10.1016/j.bmc.2014.02.030.
Zi-Hong Yan  1 ,  Xia-Yun Huang  1 ,  Hai-Qiu Wu  1 ,  Wen-Xue Chen  1 ,  Qiu-Qin He  2 ,  Fen-Er Chen  3 ,  Erik De Clercq  4 ,  Christophe Pannecouque  4
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. Electronic address: [email protected].
  • 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. Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
PMID: 24680058 DOI: 10.1016/j.bmc.2014.02.030
Abstract

A series of CR2(OH)-diarylpyrimidine derivatives (CR2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC50 values ranging from 7.21±1.99 to 0.067±0.006 μM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC50=0.067±0.006 μM, SI>592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated.

Keywords
Antiviral activity; Diarylpyrimidine; HIV-1; NNRTIs; SAR.