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dc.contributor.authorRahmani, Raphael
dc.contributor.authorBan, Kung
dc.contributor.authorJones, Amy J
dc.contributor.authorFerrins, Lori
dc.contributor.authorGaname, Danny
dc.contributor.authorSykes, Melissa L
dc.contributor.authorAvery, Vicky M
dc.contributor.authorWhite, Karen L
dc.contributor.authorRyan, Eileen
dc.contributor.authorKaiser, Marcel
dc.contributor.authorCharman, Susan A
dc.contributor.authorBaell, Jonathan B
dc.date.accessioned2019-02-08T01:30:45Z
dc.date.available2019-02-08T01:30:45Z
dc.date.issued2015
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/acs.jmedchem.5b00438
dc.identifier.urihttp://hdl.handle.net/10072/101459
dc.description.abstractFrom a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure–activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol–1) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom6753
dc.relation.ispartofpageto6765
dc.relation.ispartofissue17
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume58
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode030499
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.title6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorSykes, Melissa L.
gro.griffith.authorAvery, Vicky M.
gro.griffith.authorJones, Amy J.


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