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dc.contributor.authorPapadopoulou, MVen_US
dc.contributor.authorBloomer, WDen_US
dc.contributor.authorRosenzweig, HSen_US
dc.contributor.authorWilkinson, SRen_US
dc.contributor.authorSzular, Jen_US
dc.contributor.authorKaiser, Men_US
dc.date.accessioned2016-10-04T09:36:10Z
dc.date.available2016-08-02en_US
dc.date.issued2016-08-09en_US
dc.date.submitted2016-08-19T12:07:27.866Z
dc.identifier.issn0223-5234en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/15702
dc.description.abstract3-Nitro-1H-1,2,4-triazole-based acetamides bearing a biphenyl- or a phenoxyphenyl moiety have shown remarkable antichagasic activity both in vitro and in an acute murine model, as well as substantial in vitro antileishmanial activity but lacked activity against human African trypanosomiasis. We have shown now that by inserting a methylene group in the linkage to obtain the corresponding propanamides, both antichagasic and in particular anti-human African trypanosomiasis potency was increased. Therefore, IC50 values at low nM concentrations against both T. cruzi and T. b. rhodesiense, along with huge selectivity indices were obtained. Although several propanamides were active against Leishmania donovani, they were slightly less potent than their corresponding acetamides. There was a good correlation between lipophilicity (clogP value) and trypanocidal activity, for all new compounds. Type I nitroreductase, an enzyme absent from the human host, played a role in the activation of the new compounds, which may function as prodrugs. Antichagasic activity in vivo was also demonstrated with representative propanamides.en_US
dc.description.sponsorshipThis work was supported in part by internal funds of the Radiation Medicine Department at NorthShore University HealthSystem. In addition, the Drugs for Neglected Diseases initiative (DNDi) received financial support from the Bill & Melinda Gates Foundation (BMGF) to perform the in vitro screenings against parasites.en_US
dc.format.extent895 - 904en_US
dc.relation.ispartofEuropean Journal of Medicinal Chemistryen_US
dc.rightsOpen Access funded by Bill & Melinda Gates Foundation Under a Creative Commons
dc.titleNitrotriazole-based acetamides and propanamides with broad spectrum antitrypanosomal activityen_US
dc.typeArticle
dc.rights.holder© 2016 The Author(s).
dc.identifier.doi10.1016/j.ejmech.2016.08.002en_US
pubs.notesNo embargoen_US
pubs.notesThis paper is listed as Open Access on the European Journal of Medicinal Chemistry websiteen_US
pubs.publication-statusPublisheden_US
pubs.volume123en_US
dcterms.dateAccepted2016-08-02en_US


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