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

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 21; pp. 4903 - 4909
• Main Authors: Ghosh, Arun K., Takayama, Jun, Kassekert, Luke A., Ella-Menye, Jean-Rene, Yashchuk, Sofiya, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2015; Elsevier
• Subjects: Antiviral; BASIC BIOLOGICAL SCIENCES; Catalytic Domain - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Design; Dose-Response Relationship, Drug; Drug Design; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 protease; Inhibitors; Isophthalamide; Life Sciences & Biomedicine; Ligands; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Phthalic Acids - chemical synthesis; Phthalic Acids - chemistry; Phthalic Acids - pharmacology; Physical Sciences; Science & Technology; Structure-Activity Relationship; Synthesis; Design; Isophthalamide; Antiviral; Inhibitors; Synthesis; HIV-1 protease; RESOLUTION CRYSTAL-STRUCTURES; RESISTANT HIV; LIGANDS; ACTIVE ANTIRETROVIRAL THERAPY; INFECTION; BETA-SECRETASE INHIBITORS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.05.052

[Display omitted] 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 0.17nM and antiviral IC50 of 14nM. 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.