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

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 α-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 α-aminophosphonates tested here operate in a non-competitive manner.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03096017
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Submitted on : Monday, January 4, 2021 - 6:40:56 PM
Last modification on : Friday, January 8, 2021 - 3:34:58 AM

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Zexin Chen, Patricia Marcé, Ricardo Resende, Pedro Alzari, A. Carlos Frasch, et al.. The synthesis and kinetic evaluation of aryl α-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase. European Journal of Medicinal Chemistry, Elsevier, 2018, 158, pp.25-33. ⟨10.1016/j.ejmech.2018.08.089⟩. ⟨pasteur-03096017⟩

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