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α‐Ketoheterocycles as Inhibitors of Leishmania mexicana Cysteine Protease CPB
Author(s) -
Steert Koen,
Berg Maya,
Mottram Jeremy C.,
Westrop Gareth D.,
Coombs Graham H.,
Cos Paul,
Maes Louis,
Joossens Jurgen,
Van der Veken Pieter,
Haemers Achiel,
Augustyns Koen
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000265
Subject(s) - proteases , cysteine protease , cysteine , protease , leishmania mexicana , leishmania , biochemistry , cysteine proteinase inhibitors , antiparasitic agent , biology , protease inhibitor (pharmacology) , leishmaniasis , enzyme , chemistry , virology , pharmacology , immunology , parasite hosting , virus , caspase , apoptosis , programmed cell death , world wide web , computer science , antiretroviral therapy , viral load
Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas disease, and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinylsulfone‐based cysteine protease inhibitors, a series of α‐ketoheterocycles were developed as reversible inhibitors of a recombinant L. mexicana cysteine protease, CPB2.8. Three isoxazoles and especially one oxadiazole compound are potent reversible inhibitors of CPB2.8; however, in vitro whole‐organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.