2. Academic Validation
  3. Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: Design, synthesis and biological activities

Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: Design, synthesis and biological activities

  • Eur J Med Chem. 2023 Feb 15;248:115114. doi: 10.1016/j.ejmech.2023.115114.
Wei Ming 1,  Wen-Long Lu 1,  Christophe Pannecouque 2,  Jiong Chen 1,  Hai-Feng Wang 3,  Ya-Qi Xiao 1,  Sha Hu 1,  Shuang-Xi Gu 4,  Yuan-Yuan Zhu 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 KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000, Leuven, Belgium.
  • 3 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China; Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan, 430205, China.
  • 4 Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China; Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: [email protected].
  • 5 School of Chemistry and Environmental Engineering, 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; Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: [email protected].
PMID: 36640458 DOI: 10.1016/j.ejmech.2023.115114
Abstract

The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were designed from two excellent HIV-1 NNRTIs delavirdine and piperidin-4-yl-aminopyrimidine via molecular hybridization. The target compounds 4a-r were prepared and evaluated for their cellular anti-HIV activities and cytotoxicities as well as the inhibitory activities against HIV-1 Reverse Transcriptase (RT). All the newly synthesized compounds demonstrated moderate to excellent potency against wild-type (WT) HIV-1 with EC50 values in a range of 5.7 to 0.0086 μM and against RT with IC50 values ranging from 12.0 to 0.11 μM, indicating that the DPAPYs were specific RT inhibitors. Among all, 4d displayed the most potent activity against WT HIV-1 (EC50 = 8.6 nM, SI = 2151). Gratifyingly, it exhibited good to excellent potency against the single HIV-1 mutants L100I, K103N, Y181C, Y188L, E138K, as well as the double mutant F227L + V106A. Furthermore, the preliminary structure-activity relationships were summarized, molecular modeling was conducted to explore the binding mode of DPAPYs and HIV-1 RT, and their physicochemical properties were also predicted.

Keywords

HIV-1 inhibitors; Molecular hybridization; NNRTIs; Reverse transcriptase; SARs.

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