Antiviral agents 2. Synthesis of trimeric naphthoquinone analogues of conocurvone and their antiviral evaluation against HIV

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 17; pp. 6442 - 6450
• Main Authors: Crosby, Ian T., Bourke, David G., Jones, Eric D., de Bruyn, Paula J., Rhodes, David, Vandegraaff, Nick, Cox, Susan, Coates, Jonathan A.V., Robertson, Alan D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-09-2010; Elsevier
• Subjects: Animals; Anti-HIV activity; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Conocurvone; HIV Integrase - metabolism; HIV integrase inhibition; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - pharmacology; HIV-1 - enzymology; Humans; Medical sciences; Naphthoquinone trimers; Naphthoquinones - chemical synthesis; Naphthoquinones - pharmacology; Pharmacology. Drug treatments; Rats; Anti-HIV activity; Conocurvone; Naphthoquinone trimers; HIV integrase inhibition; Intravenous administration; Oxygen heterocycle; Integrase inhibitor; Structure activity relation; Bicyclic compound; Antiviral; Chemical synthesis; Trimer; Enzyme; Transferases; Quinone; Oral administration; Retroviridae; Enzyme inhibitor; Naphthoquinone derivatives; Tricyclic compound; Lentivirus; Condensed benzenic compound; In vitro; Virus; In vivo; Nucleotidyltransferases; Animal; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.105

The synthesis of a new series of conocurvone analogues is presented that explores the importance of the pyran rings of conocurvone, their degree of unsaturation as well as the role of alkoxy functionalities as pyran ring replacements, for the inhibition of the HIV-1 integrase (IN) enzyme. Difficulties in synthesising a trimeric naphthoquinone where the central quinone bears a
peri-dihydropyran ring was attributed to distortion of the electrophilic dihaloquinone successfully utilised in the past. Increased electron density could also be a factor in reducing reactivity. The desired central dihydropyran bearing trimeric naphthoquinone was successfully synthesised by using a more reactive bromo-tosyloxyquinone intermediate. A maleimide derivative, where the central quinone between the pendant hydroxyquinones was replaced, was successfully synthesised and although it exhibited comparable enzyme inhibitory activity it had negligible HIV inhibitory cellular activity. Compounds were assessed for activity in both in vitro assays using purified recombinant HIV-1 IN and demonstrated superior or comparable activity to conocurvone derivatives previously reported.