title: Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT).
abstract: We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105-3678, United States.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: David
authors.initials: D
authors.lastname: Smithson
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Gloria
authors.initials: G
authors.lastname: Holbrook
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D013329:Structure-Activity Relationship; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D001549:Benzamides