2. Academic Validation
  3. Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities

  • Eur J Med Chem. 2020 Jan 15;186:111864. doi: 10.1016/j.ejmech.2019.111864.
Ting Xiao 1,  Jia-Fan Tang 1,  Ge Meng 2,  Christophe Pannecouque 3,  Yuan-Yuan Zhu 4,  Gen-Yan Liu 1,  Zhi-Qiang Xu 1,  Feng-Shou Wu 1,  Shuang-Xi Gu 5,  Fen-Er Chen 6
Affiliations

Affiliations

  • 1 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China.
  • 2 Department of Chemistry, Fudan University, Shanghai, 200433, China.
  • 3 KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000, Leuven, Belgium.
  • 4 School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan, 430205, China.
  • 5 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: [email protected].
  • 6 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China; Department of Chemistry, Fudan University, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 31767136 DOI: 10.1016/j.ejmech.2019.111864
Abstract

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 μM), Y181C (EC50 = 0.11 μM), E138K (EC50 = 0.057 μM), and moderate activity against double mutants RES056 (EC50 = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 Reverse Transcriptase.

Keywords

AIDS; Anti-HIV; Diaryl ethers; Indazole analogues; Molecular hybridization; NNRTIs; Piperidin-4-yl-aminopyrimidines.

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