title: Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei.
abstract: We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50=120nM for Trypanosoma b. brucei, 18nM for Trypanosoma b. rhodesiense, and 38nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50>25μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2>4h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.
authors.affiliation: St. Jude Children's Hospital, Department of Chemical Biology and Therapeutics, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: David C
authors.initials: DC
authors.lastname: Smithson
authors.forename: Gloria
authors.initials: G
authors.lastname: Holbrook
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
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
authors.initials: R
authors.lastname: Kiplin Guy
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002460:Cell Line; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D012995:Solubility; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D001549:Benzamides; D014344:Trypanocidal Agents; C037689:benzamide