Abstract
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 microM) and biologically active against bloodstream T. brucei (EC(50)=10 microM), but with poor selectivity against mammalian MRC5 cells (EC(50)=29 microM). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Line
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology
-
Humans
-
NADH, NADPH Oxidoreductases / antagonists & inhibitors*
-
NADH, NADPH Oxidoreductases / metabolism
-
Phencyclidine / analogs & derivatives*
-
Phencyclidine / chemical synthesis
-
Phencyclidine / pharmacology
-
Piperidines / chemical synthesis*
-
Piperidines / chemistry
-
Piperidines / pharmacology
-
Structure-Activity Relationship
-
Thiophenes / chemical synthesis*
-
Thiophenes / chemistry
-
Thiophenes / pharmacology
-
Trypanocidal Agents / chemical synthesis*
-
Trypanocidal Agents / chemistry
-
Trypanocidal Agents / pharmacology
-
Trypanosoma brucei brucei / drug effects
-
Trypanosoma brucei brucei / enzymology
Substances
-
1-(1-(benzo(b)thiophen-2-yl)cyclohexyl)piperidine
-
Enzyme Inhibitors
-
Piperidines
-
Thiophenes
-
Trypanocidal Agents
-
NADH, NADPH Oxidoreductases
-
trypanothione reductase
-
Phencyclidine