Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

  • Bioorg Med Chem Lett. 2015 Nov 1;25(21):4903-4909. doi: 10.1016/j.bmcl.2015.05.052.
Arun K Ghosh  1 ,  Jun Takayama  2 ,  Luke A Kassekert  2 ,  Jean-Rene Ella-Menye  2 ,  Sofiya Yashchuk  2 ,  Johnson Agniswamy  3 ,  Yuan-Fang Wang  3 ,  Manabu Aoki  4 ,  Masayuki Amano  4 ,  Irene T Weber  3 ,  Hiroaki Mitsuya  5
Affiliations
  • 1. Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: [email protected].
  • 2. Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 3. Departments of Biology and Chemistry, Georgia State University, Atlanta, GA 30303, USA.
  • 4. Departments of Hematology and Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan.
  • 5. Departments of Hematology and Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA; Center for Clinical Sciences, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan.
PMID: 26096678 DOI: 10.1016/j.bmcl.2015.05.052
Abstract

We describe the design, synthesis and biological evaluation of a series of novel HIV-1 Protease Inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good Antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and Antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11Å resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

Keywords
Antiviral; Design; HIV-1 protease; Inhibitors; Isophthalamide; Synthesis.