Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors. / Spinks, Daniel; Torrie, Leah S.; Thompson, Stephen; Harrison, Justin R.; Frearson, Julie A.; Read, Kevin D.; Fairlamb, Alan H.; Wyatt, Paul G.; Gilbert, Ian H.
In: ChemMedChem, Vol. 7, No. 1, 02.01.2012, p. 95-106.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors
AU - Spinks,Daniel
AU - Torrie,Leah S.
AU - Thompson,Stephen
AU - Harrison,Justin R.
AU - Frearson,Julie A.
AU - Read,Kevin D.
AU - Fairlamb,Alan H.
AU - Wyatt,Paul G.
AU - Gilbert,Ian H.
PY - 2012/1/2
Y1 - 2012/1/2
N2 - <p>Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62?000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.</p>
AB - <p>Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62?000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.</p>
KW - antiprotozoal agents
KW - drug design
KW - Trypanosoma brucei
KW - trypanothione synthetase
KW - HUMAN AFRICAN TRYPANOSOMIASIS
KW - DRUG TARGET
KW - METABOLISM
KW - REDUCTASE
KW - BIOSYNTHESIS
KW - LEISHMANIA
KW - LEAD
U2 - 10.1002/cmdc.201100420
DO - 10.1002/cmdc.201100420
M3 - Article
VL - 7
SP - 95
EP - 106
JO - ChemMedChem
T2 - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 1
ER -