Synthesis and Antiviral Activity of New Anti-HIV Amprenavir Bioisosteres

• Published in: Journal of medicinal chemistry Vol. 45; no. 15; pp. 3321 - 3324
• Main Authors: Rocheblave, Luc, Bihel, Frédéric, De Michelis, Céline, Priem, Ghislaine, Courcambeck, Jérôme, Bonnet, Brice, Chermann, Jean-Claude, Kraus, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 18-07-2002
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Carbamates; Cell Line; Chemical Sciences; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; Humans; Medical sciences; Medicinal Chemistry; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemistry; Virus Replication; Sulfonamide; HIV-1 virus; Enzyme; Benzene derivatives; Furan derivatives; Retroviridae; Enzyme inhibitor; Virus replication cycle; Oxygen heterocycle; Lentivirus; In vitro; Virus; Peptidases; Structure activity relation; Hydrolases; Antiviral; Human immunodeficiency virus; Inhibition; Secondary alcohol; Chemical synthesis; Diastereomer; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0208323

Starting from the chemical structure of the recent FDA-approved anti-HIV drug Amprenavir (Agenerase), a potent HIV-protease inhibitor, we have designed new series of Amprenavir bioisoteres in which the methylene group of the benzyl group was replaced by a sulfur atom. This structural modification has required an original multistep synthesis. Unfortunately, introduction of the sulfur atom abolished or drastically decreased both inhibitory activity on recombinant HIV protease and HIV infection protection on MT4 cell cultures.