New 2-arylnaphthalenediols and triol inhibitors of HIV-1 integrase—Discovery of a new polyhydroxylated antiviral agent

• Published in: Bioorganic & medicinal chemistry 2010-07, Vol.18 (14), p.5194-5201
• Main Authors: Maurin, Cédric, Lion, Cédric, Bailly, Fabrice, Touati, Nadia, Vezin, Hervé, Mbemba, Gladys, Mouscadet, Jean François, Debyser, Zeger, Witvrouw, Myriam, Cotelle, Philippe
• Format: Article
• Language: English
• Subjects: 6-Arylnaphthalene-1,2-diols; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Chemical Sciences; HIV Infections - drug therapy; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 Integrase inhibitors; Humans; Material chemistry; Medical sciences; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; or physical chemistry; Pharmacology. Drug treatments; Theoretical and
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.05.059

A series of 13 hydroxylated 2-arylnaphthalenes has been synthesized and evaluated as HIV-1 integrase inhibitors. 7-(3,4,5-Trihydroxyphenyl)naphthalene-1,2,3-triol was converted to a dimer. This dimer displays submicromolar activity against HIV-1 IN and was found to present antiviral properties with a low cytotoxicity on two different cell lines. A series of 13 hydroxylated 2-arylnaphthalenes have been synthesized and evaluated as HIV-1 integrase inhibitors. 7-(3,4,5-Trihydroxyphenyl)naphthalene-1,2,3-triol 1c revealed chemical instability upon storage, leading to the isolation of a dimer 5c which was also tested. In the 2-arylnaphthalene series, all compounds were active against HIV-1 IN with IC50’s within the 1–10μM range, except for 1c and 5c which displayed submicromolar activity. Antiviral activity against HIV-1 replication was measured on 1b–c and 5c. Amongst the tested molecules, only 5c was found to present antiviral properties with a low cytotoxicity on two different cell lines.