Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase

被引：11

作者：

Duyzend, Michael H. ^{[1
]}

Clark, Christopher T. ^{[1
]}

Simmons, Shayna L. ^{[1
]}

Johnson, Wade B. ^{[1
]}

Larson, Anna M. ^{[1
]}

Leconte, Aaron M. ^{[1
]}

Wills, Andrew W. ^{[1
]}

Ginder-Vogel, Matthew ^{[1
]}

Wilhelm, April K. ^{[1
]}

Czechowicz, Josephine A. ^{[1
]}

Alberg, David G. ^{[1
]}

机构：

[1] Carleton Coll, Dept Chem, Northfield, MN 55057 USA

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2012年 / 27卷 / 06期

基金：

美国国家卫生研究院;

关键词：

Trypanothione reductase; inhibitors; Trypanosoma cruzi; trypanosome; HUMAN GLUTATHIONE-REDUCTASE; TRYPANOSOMA-CRUZI; CRITHIDIA-FASCICULATA; COUPLING REAGENT; OXIDATIVE STRESS; BINDING-SITE; PURIFICATION; ENZYME; CONVENIENT; DRUGS;

D O I：

10.3109/14756366.2011.604319

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K-i = 2 mu M.

引用

页码：784 / 794

页数：11

共 50 条

[1] Synthesis and Evaluation of Indatraline-Based Inhibitors for Trypanothione Reductase
Walton, Jeffrey G. A.
Jones, Deuan C.
Kiuru, Paula
Durie, Alastair J.
Westwood, Nicholas J.
Fairlamb, Alan H.
CHEMMEDCHEM, 2011, 6 (02) : 321 - 328
[2] Synthesis and testing of inhibitors of trypanothione reductase
Czechowicz, J
Alberg, DG
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2004, 227 : U631 - U631
[3] Synthesis of trypanothione reductase inhibitors.
Spalding, MD
Alberg, DG
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2003, 225 : U413 - U413
[4] SYNTHESIS OF SUBSTRATE-ANALOGS FOR TRYPANOTHIONE REDUCTASE
ELWAER, AF
BENSON, T
DOUGLAS, KT
INTERNATIONAL JOURNAL OF PEPTIDE AND PROTEIN RESEARCH, 1993, 41 (02): : 141 - 146
[5] Synthesis of novel trypanothione reductase inhibitors.
Ginder-Vogel, MA
Alberg, DG
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 219 : U348 - U348
[6] Trypanothione reductase inhibitors
Edwards, P
DRUG DISCOVERY TODAY, 2001, 6 (01) : 54 - 54
[7] Synthesis, biological evaluation and molecular modeling of arylfurans as potential trypanothione reductase inhibitors
de Oliveira, Renata B.
Zani, Carlos L.
Ferreira, Rafaela S.
Leite, Rodrigo S.
Alves, Tania M. A.
da Silva, Thais H. A.
Romanha, Alvaro J.
QUIMICA NOVA, 2008, 31 (02): : 261 - 267
[8] The synthesis of parasitic cysteine protease and trypanothione reductase inhibitors
Chibale, K
Musonda, CC
CURRENT MEDICINAL CHEMISTRY, 2003, 10 (18) : 1863 - 1889
[9] Substrate specificity of trypanothione reductase
Marsh, IR
Bradley, M
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 243 (03): : 690 - 694
[10] Substrate specificity of trypanothione reductase
Marsh, I. R.
Bradley, M.
European Journal of Biochemistry, 243 (03):

← 1 2 3 4 5 →