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Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis.
ChemMedChem. 2009 Aug; 4(8):1333-40.C

Abstract

Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (K(i)=330 nM) with an improved potency against T. brucei (EC(50)=775 nM).

Authors+Show Affiliations

Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19557801

Citation

Richardson, John L., et al. "Improved Tricyclic Inhibitors of Trypanothione Reductase By Screening and Chemical Synthesis." ChemMedChem, vol. 4, no. 8, 2009, pp. 1333-40.
Richardson JL, Nett IR, Jones DC, et al. Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. ChemMedChem. 2009;4(8):1333-40.
Richardson, J. L., Nett, I. R., Jones, D. C., Abdille, M. H., Gilbert, I. H., & Fairlamb, A. H. (2009). Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. ChemMedChem, 4(8), 1333-40. https://doi.org/10.1002/cmdc.200900097
Richardson JL, et al. Improved Tricyclic Inhibitors of Trypanothione Reductase By Screening and Chemical Synthesis. ChemMedChem. 2009;4(8):1333-40. PubMed PMID: 19557801.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improved tricyclic inhibitors of trypanothione reductase by screening and chemical synthesis. AU - Richardson,John L, AU - Nett,Isabelle R E, AU - Jones,Deuan C, AU - Abdille,Mohamed H, AU - Gilbert,Ian H, AU - Fairlamb,Alan H, PY - 2009/6/27/entrez PY - 2009/6/27/pubmed PY - 2009/10/29/medline SP - 1333 EP - 40 JF - ChemMedChem JO - ChemMedChem VL - 4 IS - 8 N2 - Trypanothione reductase (TryR) is a key validated enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes and leishmania parasites. This system is absent in humans, being replaced with glutathione and glutathione reductase, and as such offers a target for selective inhibition. As part of a program to discover antiparasitic drugs, the LOPAC1280 library of 1266 compounds was screened against TryR and the top hits evaluated against glutathione reductase and T. brucei parasites. The top hits included a number of known tricyclic neuroleptic drugs along with other new scaffolds for TryR. Three novel druglike hits were identified and SAR studies on one of these using information from the tricyclic neuroleptic agents led to the discovery of a competitive inhibitor (K(i)=330 nM) with an improved potency against T. brucei (EC(50)=775 nM). SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/19557801/Improved_tricyclic_inhibitors_of_trypanothione_reductase_by_screening_and_chemical_synthesis_ L2 - https://doi.org/10.1002/cmdc.200900097 DB - PRIME DP - Unbound Medicine ER -