Screening of acyl hydrazide proteinase inhibitors for antiparasitic activity against Trypanosoma brucei

International Journal of Antimicrobial Agents
Conor R CaffreyDietmar Steverding

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.

References

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Citations

Aug 21, 2003·International Journal of Antimicrobial Agents·Njinkeng Joseph NkemguDietmar Steverding
Jan 24, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Muhammad TahaMuhammad Iqbal Choudhary
Jul 30, 2005·Expert Opinion on Investigational Drugs·Dietmar Steverding, Kevin M Tyler
Sep 11, 2004·Bioorganic & Medicinal Chemistry Letters·A RyckebuschP Melnyk
Dec 19, 2018·Pharmaceutical Research·Helen W HernandezSean Ekins
Nov 11, 2003·Journal of Combinatorial Chemistry·Roland E Dolle
Apr 25, 2013·Journal of Medicinal Chemistry·Roberta EttariPaola Conti
Aug 18, 2009·Bioorganic & Medicinal Chemistry·José Mauricio dos Santos FilhoLucia Fernanda C C Leite

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