title: 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis.
abstract: A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
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.forename: Raphaël
authors.initials: R
authors.lastname: Rahmani
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Sykes
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Jones
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: Eliott
authors.initials: E
authors.lastname: Teston
authors.forename: Basmah
authors.initials: B
authors.lastname: Almohaywi
authors.forename: JieXiang
authors.initials: J
authors.lastname: Yin
authors.forename: Jason
authors.initials: J
authors.lastname: Smith
authors.forename: Chris
authors.initials: C
authors.lastname: Hyland
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D006801:Humans; D051379:Mice; D032448:Myoblasts, Skeletal / Q000187:drug effects; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000469:parasitology*
chemical_list: D000813:Anilides; D014344:Trypanocidal Agents
keywords: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; BBB; DCM; DMAP; DMEM; DMF; Dulbecco's modified Eagle's medium; E(H); EDCI; FCS; HAT; HBTU; HEPES; Human African trypanosomiasis; L. donovani; Leishmania Donovani; N,N-dimethylaminopyridine; N,N-dimethylformamide; O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; P. falciparum; Plasmodium falciparum; STPHI; Sleeping sickness; Swiss Tropical and Public Health Institute; T.b. brucei; T.b. gambiense; T.b. rhodesiense; TBAB; Trypanosoma brucei; Trypanosoma brucei brucei; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomacidal agent; WHO; World Health Organisation; blood–brain barrier; cPPB; chromatographic plasma protein binding; cytotox.; cytotoxicity; dichloromethane; foetal calf serum; hepatic extraction; human African trypanosomiasis; tetrabutylammonium bromide