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Synthesis and Evaluation of 1‐(1‐(Benzo[ b ]thiophen‐2‐yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase
Author(s) -
Patterson Stephen,
Jones Deuan C.,
Shanks Emma J.,
Frearson Julie A.,
Gilbert Ian H.,
Wyatt Paul G.,
Fairlamb Alan H.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900098
Subject(s) - piperidine , stereochemistry , chemistry , enzyme , enzyme inhibitor , biochemistry
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[ b ]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme ( K i =1 μ M ) and biologically active against bloodstream T. brucei (EC 50 =10 μ M ), but with poor selectivity against mammalian MRC5 cells (EC 50 =29 μ M ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed.