Show simple item record

dc.contributor.authorRussell, Stephanie
dc.contributor.authorRahmani, Raphael
dc.contributor.authorJones, Amy J
dc.contributor.authorNewson, Harriet L
dc.contributor.authorNeilde, Kevin
dc.contributor.authorCotillo, Ignacio
dc.contributor.authorKhajouei, Marzieh Rahmani
dc.contributor.authorFerrins, Lori
dc.contributor.authorQureishi, Sana
dc.contributor.authorNghi, Nguyen
dc.contributor.authorMartinez-Martinez, Maria S
dc.contributor.authorWeaver, Donald F
dc.contributor.authorKaiser, Marcel
dc.contributor.authorRiley, Jennifer
dc.contributor.authorThomas, John
dc.contributor.authorDe Rycker, Manu
dc.contributor.authorRead, Kevin D
dc.contributor.authorFlematti, Gavin R
dc.contributor.authorRyan, Eileen
dc.contributor.authorTanghe, Scott
dc.contributor.authorRodriguez, Ana
dc.contributor.authorCharman, Susan A
dc.contributor.authorKessler, Albane
dc.contributor.authorAvery, Vicky M
dc.contributor.authorBaell, Jonathan B
dc.contributor.authorPiggott, Matthew J
dc.date.accessioned2017-11-20T03:57:49Z
dc.date.available2017-11-20T03:57:49Z
dc.date.issued2016
dc.identifier.issn0022-2623
dc.identifier.doi10.1021/acs.jmedchem.6b00442
dc.identifier.urihttp://hdl.handle.net/10072/143276
dc.description.abstractThe parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure–activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom9686
dc.relation.ispartofpageto9720
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.relation.ispartofvolume59
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.titleHit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorAvery, Vicky M.
gro.griffith.authorJones, Amy J.


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record