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 |
|---|---|
| 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 |
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Keywords
- Inhibitors
- Non-competitive
- Trans-sialidase
- Trypanosoma cruzi
- α-aminophosphonates
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
The synthesis and kinetic evaluation of aryl α-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 journal › Article
}
TY - JOUR
T1 - The synthesis and kinetic evaluation of aryl α-aminophosphonates as novel inhibitors of T. cruzi trans-sialidase
AU - Chen, Zexin
AU - Marce Villa, Patricia
AU - Resende, Ricardo
AU - Alzari, Pedro M.
AU - Frasch, A. Carlos
AU - Van Den Elsen, Johannes
AU - Crennell, Susan
AU - Watts, Andrew
PY - 2018/10/5
Y1 - 2018/10/5
N2 - 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.
AB - 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.
KW - Inhibitors
KW - Non-competitive
KW - Trans-sialidase
KW - Trypanosoma cruzi
KW - α-aminophosphonates
UR - http://www.scopus.com/inward/record.url?scp=85052974769&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.08.089
DO - 10.1016/j.ejmech.2018.08.089
M3 - Article
VL - 158
SP - 25
EP - 33
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -