The synthesis and kinetic evaluation of aryl a-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase

Zexin Chen, Patricia Marce Villa, Ricardo Resende, Pedro M. Alzari, A. Carlos Frasch, Johannes Van Den Elsen, Susan Crennell, Andrew Watts

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Abstract

The trans-sialidase protein expressed by Trypanosoma cruzi is an important enzyme in the life cycle of this human pathogenic parasite and is considered a promising target for the development of new drug treatments against Chagas' disease. Here we describe a-amino phosphonates as a novel class of inhibitor of T. cruzi trans-sialidase. Molecular modelling studies were initially used to predict the active-site binding affinities for a series of amino phosphonates, which were subsequently synthesised and their IC50s determined in vitro. The measured inhibitory activities show some correlation with the predictions from molecular modelling, with 1-napthyl derivatives found to be the most potent inhibitors having IC50s in the low micromolar range. Interestingly, kinetic analysis of the mode of inhibition demonstrated that the a-aminophosphonates tested here operate in a non-competitive manner.
Original languageEnglish
Pages (from-to)25-33
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume158
Early online date31 Aug 2018
DOIs
Publication statusPublished - 5 Oct 2018

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Organophosphonates
Molecular modeling
Drug therapy
Kinetics
Chagas Disease
Trypanosoma cruzi
Life Cycle Stages
Life cycle
Catalytic Domain
Parasites
Binding Sites
Derivatives
Enzymes
Pharmaceutical Preparations
Proteins
trans-sialidase
In Vitro Techniques

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The synthesis and kinetic evaluation of aryl a-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase. / Chen, Zexin; Marce Villa, Patricia; Resende, Ricardo; Alzari, Pedro M.; Frasch, A. Carlos; Van Den Elsen, Johannes; Crennell, Susan; Watts, Andrew.

In: European Journal of Medicinal Chemistry, Vol. 158, 05.10.2018, p. 25-33.

Research output: Contribution to journalArticle

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