title: Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides.
abstract: The 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.
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Russell
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rahmani
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane Innovation Park, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Jones
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Harriet L
authors.initials: HL
authors.lastname: Newson
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.|GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Kevin
authors.initials: K
authors.lastname: Neilde
authors.affiliation: GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Cotillo
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Rahmani Khajouei
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Lori
authors.initials: L
authors.lastname: Ferrins
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Sana
authors.initials: S
authors.lastname: Qureishi
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Nghi
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Martinez-Martinez
authors.affiliation: Department of Chemistry, Dalhousie University , Halifax Nova Scotia B3H 4R2, Canada.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Weaver
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse, 4051 Basel, Switzerland.|University of Basel , Petesplatz 1, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , DD1 5EH Dundee, U.K.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Riley
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , DD1 5EH Dundee, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , DD1 5EH Dundee, U.K.
authors.forename: Manu
authors.initials: M
authors.lastname: De Rycker
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , DD1 5EH Dundee, U.K.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Flematti
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: Anti-Infectives Screening Core, New York University School of Medicine , New York, New York 10010, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Tanghe
authors.affiliation: Anti-Infectives Screening Core, New York University School of Medicine , New York, New York 10010, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.|Centre for Drug Candidate Optimisation, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: GlaxoSmithKline , 28760 Tres Cantos, Spain.
authors.forename: Albane
authors.initials: A
authors.lastname: Kessler
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University , Brisbane Innovation Park, Don Young Road, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia , 35 Stirling Highway, Crawley, Perth 6009, Western Australia, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Piggott
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D058886:Sterol 14-Demethylase / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D014344:Trypanocidal Agents; D058886:Sterol 14-Demethylase