naphthoquinones and conocurvone

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.

Topics: Animals; Anti-HIV Agents; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Naphthoquinones; Rats

Unsymmetrical biquinone and trimeric quinone derivatives were synthesized using halotriflate-biselectrophilic naphthoquinones through stepwise regioselective quinone substitution chemistry and evaluated for their ability to inhibit the cytopathogenic effects of HIV-1 using an MTT colorimetric assay. Compounds were also screened for their ability to inhibit the activity of HIV-1 integrase in vitro. Pyranylated trimeric quinones and biquinones exhibited both antiviral activity and integrase inhibitory activity. Conocurvone 1 and trimeric quinone 21 were the most potent HIV integrase inhibitors in the series. All of the biquinones showed HIV inhibitory activity. Simple methoxy substituted biquinones did not inhibit HIV-1 integrase.

Topics: Anti-HIV Agents; Colorimetry; HIV Integrase; Molecular Structure; Naphthoquinones; Quinones; Stereoisomerism

[reaction: see text] The trimeric quinone framework of conocurvone is crucial for its potent anti-HIV activity. A new synthesis of trimeric quinones based on stepwise substitution of the halogens in 2,3-dihaloquinones by hydroxyquinone anions is described. Chlorinated biquinones are key intermediates that undergo regiospecific substitution reactions to yield trimeric quinone monomethyl ethers.

Topics: Anti-HIV Agents; Filtration; Indicators and Reagents; Magnetic Resonance Spectroscopy; Naphthoquinones; Quinones; Stereoisomerism

During the reisolation of the trimeric naphthoquinone derivative conocurvone [1] from an extract of the Australian shrub Conospermum incurvum, six monomeric naphthoquinones were isolated. These include three novel 1,4-naphthoquinone derivatives: 3-methyl-14,15-dihydro-15-hydroxyteretifolione B [3], 3-methyl-14,15-dihydro-15-hydroxyteretifolione B methyl ether [4], and 2,3-dimethyl-6-hydroxy-7-methoxy-1,4-naphthoquinone [5]. In addition, the previously reported compounds 3-methylteretifolione B [6], 3-methylteretifolione B methyl ether [7], and 8-geranyl-2,7-dihydroxy-3-methyl-1,4-naphthoquinone [8] were isolated and identified. The structures of the novel 1,4-naphthoquinones were elucidated by spectral methods. While conocurvone [1] is a potent inhibitor of HIV-1-induced cell killing, all of the monomeric naphthoquinone derivatives were inactive against HIV-1.

Topics: Antiviral Agents; Australia; Cell Survival; HIV-1; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Naphthoquinones; Plant Roots; Plants