The synthesis and kinetic evaluation of aryl alpha-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase.
Chen, Z., Marce, P., Resende, R., Alzari, P. M., Frasch, A. C., van den Elsen, J. M. H., Crennell, S. J. and Watts, A. G.
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
Institut Pasteur, Unite de Microbiologie Structurale, CNRS URA 3528 & Universite Paris Diderot, 25 Rue de Dr. Roux, 75724, Paris, France.
Instituto de Investigaciones Biotecnologicas, Universidad de General San Martin, Casilla de Correo 30, 1650 San Martin, Argentina.
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. Electronic address:
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 alpha-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 alpha-aminophosphonates tested here operate in a non-competitive manner.
European Journal of Medicinal Chemistry 158: 25-33 (2018)