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Crosby I.T.,Monash Institute of Pharmaceutical Sciences | Bourke D.G.,Monash Institute of Pharmaceutical Sciences | Jones E.D.,Monash Institute of Pharmaceutical Sciences | Jeynes T.P.,Monash Institute of Pharmaceutical Sciences | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

The discovery of a small molecule non-nucleoside inhibitor of Hepatitis B Virus is described. During our work on conocurvone derived naphthoquinone 'trimers' for the treatment of HIV, we discovered a potent inhibitor 9 of Hepatitis B Virus in an antiviral screen. During attempts to resynthesis 9 for proof of concept studies, we altered the synthesis in order to attempt to reduced side reactions and difficult to remove by-products. As a result we discovered a small molecule 19 that also was a potent inhibitor of HBV. Importantly, this small molecule inhibitor of Hepatitis B Virus is also an inhibitor of Hepatitis B Virus resistant to 3TC, a bench mark of nucleoside analogues active in the treatment of Hepatitis B Virus. The development of 19 as an agent to treat HBV infections is discussed. © 2010 Elsevier Ltd. All rights reserved.


Crosby I.T.,Monash Institute of Pharmaceutical Sciences | Bourke D.G.,Monash Institute of Pharmaceutical Sciences | Jones E.D.,Monash Institute of Pharmaceutical Sciences | De Bruyn P.J.,Monash Institute of Pharmaceutical Sciences | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

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. © 2010 Elsevier Ltd. All rights reserved.


Conway R.J.,Monash Institute of Pharmaceutical Sciences | Valant C.,Monash Institute of Pharmaceutical Sciences | Christopoulos A.,Monash Institute of Pharmaceutical Sciences | Robertson A.D.,AMRAD Operations Pty Ltd | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A series of substituted 4-arylpiperidines and a smaller family of 4-aryl-1,2,3,6-tetrahydropyridines were synthesized and their biological activity at the 5-HT 2C receptor studied to determine whether either series showed noteworthy agonist activity. Structure-activity relationships were developed from the performed receptor binding assays and functional studies, and the results of the analysis are presented herein. © 2011 Elsevier Ltd. All rights reserved.

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