title: Screening of acyl hydrazide proteinase inhibitors for antiparasitic activity against Trypanosoma brucei.
abstract: The major cysteine proteinase (brucipain) of Trypanosoma brucei is a target for chemotherapy of African Sleeping Sickness. We have screened a non-peptidyl acyl hydrazide proteinase inhibitor library of 500 compounds for inhibition of brucipain. Those 21 compounds with IC(50) values of <40 microM were tested for efficacy against bloodstream forms of T. brucei in cell culture. Eight acyl hydrazides showed 50% or more inhibition of trypanosome replication at <1 microM. The trypanocidal acitivity of the most effective compounds was comparable with those of the commercial antitrypanosomal drugs suramin and diminazene aceturate. However, these acyl hydrazides exhibited varying cytotoxicity towards human HL-60 cells and therefore, only less favourable selectivity indices compared with the commercially available drugs. Nevertheless, the data support the potential of acyl hydrazides as antitrypanosomal chemotherapeutic agents for treatment of sleeping sickness.
authors.affiliation: Department of Pathology, Tropical Disease Research Unit, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Marvin
authors.initials: M
authors.lastname: Schanz
authors.forename: Njinkeng Joseph
authors.initials: NJ
authors.lastname: Nkemngu
authors.forename: Joseph
authors.initials: J
authors.lastname: Nkemgu-Njinkeng
authors.forename: Matthew
authors.initials: M
authors.lastname: Brush
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: Fred E
authors.initials: FE
authors.lastname: Cohen
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Flaherty
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Dietmar
authors.initials: D
authors.lastname: Steverding
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000469:parasitology*
chemical_list: D011480:Protease Inhibitors; D014344:Trypanocidal Agents