title: Antiviral agents 2. Synthesis of trimeric naphthoquinone analogues of conocurvone and their antiviral evaluation against HIV.
abstract: 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.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia. ian.crosby@pharm.monash.edu.au
authors.forename: Ian T
authors.initials: IT
authors.lastname: Crosby
authors.forename: David G
authors.initials: DG
authors.lastname: Bourke
authors.forename: Eric D
authors.initials: ED
authors.lastname: Jones
authors.forename: Paula J
authors.initials: PJ
authors.lastname: de Bruyn
authors.forename: David
authors.initials: D
authors.lastname: Rhodes
authors.forename: Nick
authors.initials: N
authors.lastname: Vandegraaff
authors.forename: Susan
authors.initials: S
authors.lastname: Cox
authors.forename: Jonathan A V
authors.initials: JA
authors.lastname: Coates
authors.forename: Alan D
authors.initials: AD
authors.lastname: Robertson
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D009285:Naphthoquinones; C091977:conocurvone; D019427:HIV Integrase