title: Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands.
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.
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Takayama
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Kassekert
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jean-Rene
authors.initials: JR
authors.lastname: Ella-Menye
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Sofiya
authors.initials: S
authors.lastname: Yashchuk
authors.affiliation: Departments of Biology and Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.affiliation: Departments of Biology and Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Departments of Hematology and Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Departments of Hematology and Infectious Diseases, Kumamoto University of Medicine, Kumamoto 860-8556, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.affiliation: Departments of Biology and Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.affiliation: 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.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D010795:Phthalic Acids; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Antiviral; Design; HIV-1 protease; Inhibitors; Isophthalamide; Synthesis