title: Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis.
abstract: A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24 , 2451 - 2465 ) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Donald A
authors.identifier: 0000-0001-7423-1379
authors.initials: DA
authors.lastname: Patrick
authors.forename: J Robert
authors.identifier: 0000-0002-5650-0333
authors.initials: JR
authors.lastname: Gillespie
authors.forename: Joshua
authors.initials: J
authors.lastname: McQueen
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.forename: Ranae M
authors.initials: RM
authors.lastname: Ranade
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Creason
authors.forename: Zackary M
authors.initials: ZM
authors.lastname: Herbst
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D014508:Urea / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D014344:Trypanocidal Agents; D014508:Urea