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 IC 50s 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 IC 50s 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.
Original language | English |
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Pages (from-to) | 25-33 |
Number of pages | 9 |
Journal | European Journal of Medicinal Chemistry |
Volume | 158 |
Early online date | 31 Aug 2018 |
DOIs | |
Publication status | Published - 5 Oct 2018 |
Keywords
- Inhibitors
- Non-competitive
- Trans-sialidase
- Trypanosoma cruzi
- α-aminophosphonates
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
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Dive into the research topics of 'The synthesis and kinetic evaluation of aryl α-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase'. Together they form a unique fingerprint.Profiles
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Andrew Watts
- Department of Life Sciences - Senior Lecturer
- Centre for Therapeutic Innovation
Person: Research & Teaching
Equipment
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Avance 300 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (1South)
Material and Chemical Characterisation (MC2)Facility/equipment: Equipment