TY - JOUR
T1 - Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase
AU - Volkov, Oleg A.
AU - Brockway, Anthony J.
AU - Wring, Stephen A.
AU - Peel, Michael
AU - Chen, Zhe
AU - Phillips, Margaret A.
AU - De Brabander, Jef K.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants 2R37AI034432 (to M.A.P.) and R01AI090599 (to M.A.P. and J.K.D.B.). M.A.P. and J.K.D.B. acknowledge the support of the Welch Foundation (Grants I-1257 and I-1422). M.A.P. holds the Sam G. Winstead and F. Andrew Bell Distinguished Chair in Biochemistry, and J.K.D.B. holds the Julie and Louis Beecherl, Jr. Chair in Medical Science. The authors thank Sara Schock for help with in vitro permeability studies and Thomas E. Richardson, both of Scynexis, Inc. (now Avista Pharma Solutions) for helpful medicinal chemistry discussions. The authors also thank, from UT Southwestern, Diana R. Tomchick for advice on crystallization studies, Karen MacMillan for her help in preparing the manuscript, Melissa McCoy and Bruce A. Posner for the RapidFire−mass spectrometry analysis of the enzyme assay, Lin You and Chuo Chen for LC−MS analysis of compound purity, and Shihua Zhong for performing parasite viability assays. Structural data shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/2/8
Y1 - 2018/2/8
N2 - New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.
AB - New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.
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U2 - 10.1021/acs.jmedchem.7b01654
DO - 10.1021/acs.jmedchem.7b01654
M3 - Article
C2 - 29271204
AN - SCOPUS:85041899302
SN - 0022-2623
VL - 61
SP - 1182
EP - 1203
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -