2. Academic Validation
  3. Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives

Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives

  • Bioorg Med Chem. 2014 Apr 1;22(7):2052-9. doi: 10.1016/j.bmc.2014.02.029.
Ye Tian 1,  Deping Du 1,  Diwakar Rai 1,  Liu Wang 1,  Huiqing Liu 2,  Peng Zhan 3,  Erik De Clercq 4,  Christophe Pannecouque 4,  Xinyong Liu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Educational Ministry of China), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China.
  • 2 Institute of Pharmacology, School of Medicine, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Educational Ministry of China), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 4 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Educational Ministry of China), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 24631361 DOI: 10.1016/j.bmc.2014.02.029
Abstract

In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies.

Keywords

Activity assay; HIV-1; Heterocycle; Molecular modeling; NNRTIs; Pyrazolo[1,5-a]pyrimidine; RT; Synthesis.

Figures