title: Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis.
abstract: Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.
authors.affiliation: SCYNEXIS, Inc., PO Box 12878, Research Triangle Park, NC 27709-2878, USA. bob.jacobs@scynexis.com
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jacobs
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Bakela
authors.initials: B
authors.lastname: Nare
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wring
authors.forename: Daitao
authors.initials: D
authors.lastname: Chen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Freund
authors.forename: Eric G
authors.initials: EG
authors.lastname: Gaukel
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Orr
authors.forename: Joe B
authors.initials: JB
authors.lastname: Perales
authors.forename: Matthew
authors.initials: M
authors.lastname: Jenks
authors.forename: Robert A
authors.initials: RA
authors.lastname: Noe
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Sligar
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: Nigel
authors.initials: N
authors.lastname: Yarlett
authors.forename: Robert
authors.initials: R
authors.lastname: Don
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001583:Benzoxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000302:isolation & purification; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D001549:Benzamides; D001583:Benzoxazoles; D001896:Boron Compounds; C557508:SCYX 7158