Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Stephen Patterson; Deuan C. Jones; Emma J. Shanks; Julie A. Frearson; Ian H. Gilbert; Paul G. Wyatt; Alan H. Fairlamb

doi:10.1002/cmdc.200900098

Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Stephen Patterson, Deuan C. Jones, Emma J. Shanks, Julie A. Frearson, Ian H. Gilbert, Paul G. Wyatt, Alan H. Fairlamb

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

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 mu m) and biologically active against bloodstream T brucei (EC50 = 10 mu m), but with poor selectivity against mammalian MRC5 cells (EC50 = 29 mu m). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.

Original language	English
Pages (from-to)	1341-1353
Number of pages	13
Journal	ChemMedChem
Volume	4
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.200900098
Publication status	Published - Aug 2009

Keywords

BTCP
inhibitors
medicinal chemistry
trypanosoma brucei
trypanothione reductase
DOPAMINE-UPTAKE
PHENCYCLIDINE-BINDING
TRYPANOSOMA-CRUZI
PCP ANALOGS
DERIVATIVES
KETONES
POTENT
1-<1-(2-BENZO<B>THIENYL)CYCLOHEXYL>PIPERIDINE
METABOLISM
DISCOVERY

Access to Document

10.1002/cmdc.200900098

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research
Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)
Fairlamb, A. (Investigator)
1/10/06 → 30/09/17
Project: Research

Cite this

@article{147fffb78eaf494f954e3b69a611cf8f,

title = "Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase",

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 mu m) and biologically active against bloodstream T brucei (EC50 = 10 mu m), but with poor selectivity against mammalian MRC5 cells (EC50 = 29 mu m). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.",

keywords = "BTCP, inhibitors, medicinal chemistry, trypanosoma brucei, trypanothione reductase, DOPAMINE-UPTAKE, PHENCYCLIDINE-BINDING, TRYPANOSOMA-CRUZI, PCP ANALOGS, DERIVATIVES, KETONES, POTENT, 1-<1-(2-BENZO<B>THIENYL)CYCLOHEXYL>PIPERIDINE, METABOLISM, DISCOVERY",

author = "Stephen Patterson and Jones, {Deuan C.} and Shanks, {Emma J.} and Frearson, {Julie A.} and Gilbert, {Ian H.} and Wyatt, {Paul G.} and Fairlamb, {Alan H.}",

year = "2009",

month = aug,

doi = "10.1002/cmdc.200900098",

language = "English",

volume = "4",

pages = "1341--1353",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "Wiley",

number = "8",

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TY - JOUR

T1 - Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

AU - Patterson, Stephen

AU - Jones, Deuan C.

AU - Shanks, Emma J.

AU - Frearson, Julie A.

AU - Gilbert, Ian H.

AU - Wyatt, Paul G.

AU - Fairlamb, Alan H.

PY - 2009/8

Y1 - 2009/8

N2 - 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 mu m) and biologically active against bloodstream T brucei (EC50 = 10 mu m), but with poor selectivity against mammalian MRC5 cells (EC50 = 29 mu m). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.

AB - 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 mu m) and biologically active against bloodstream T brucei (EC50 = 10 mu m), but with poor selectivity against mammalian MRC5 cells (EC50 = 29 mu m). Analogues with improved enzymatic and biological activity were obtained. The structure-activity relationships of this novel series are discussed.

KW - BTCP

KW - inhibitors

KW - medicinal chemistry

KW - trypanosoma brucei

KW - trypanothione reductase

KW - DOPAMINE-UPTAKE

KW - PHENCYCLIDINE-BINDING

KW - TRYPANOSOMA-CRUZI

KW - PCP ANALOGS

KW - DERIVATIVES

KW - KETONES

KW - POTENT

KW - 1-<1-(2-BENZO<B>THIENYL)CYCLOHEXYL>PIPERIDINE

KW - METABOLISM

KW - DISCOVERY

U2 - 10.1002/cmdc.200900098

DO - 10.1002/cmdc.200900098

M3 - Article

C2 - 19557802

SN - 1860-7179

VL - 4

SP - 1341

EP - 1353

JO - ChemMedChem

JF - ChemMedChem

IS - 8

ER -

Synthesis and Evaluation of 1-(1-(Benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) Analogues as Inhibitors of Trypanothione Reductase

Abstract

Keywords

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Projects

Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this