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  2. Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants

Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants

  • Eur J Med Chem. 2020 Jan 1;185:111866. doi: 10.1016/j.ejmech.2019.111866.
Mei Zhu 1 Ling Ma 1 Huiyu Zhou 1 Biao Dong 1 Yujia Wang 1 Zhen Wang 2 Jinming Zhou 1 Guoning Zhang 1 Juxian Wang 1 Chen Liang 2 Shan Cen 3 Yucheng Wang 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
  • 2 Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: shancen@hotmail.com.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: wangyucheng@imb.pumc.edu.cn.
Abstract

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) Protease Inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable Enzyme inhibitory and Antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable Antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.

Keywords

Antiviral activity; DRV-Resistant HIV-1 variants; HIV-1 protease inhibitors; Pyrimidine bases.

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