Time-dependent inhibitors of trypanothione reductase: Analogues of the spermidine alkaloid lunarine and related natural products

Chris J. Hamilton, Ahilan Saravanamuthu, Christiane Poupat, Alan H. Fairlamb, Ian M. Eggleston

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The macrocyclic spermidine alkaloid lunarine 1 from Lunaria biennis is a competitive, time-dependent inhibitor of the protozoan oxidoreductase trypanothione reductase (TryR), a promising target in drug design against tropical parasitic diseases. Various molecules related to I and the alkaloid itself have been synthesized in racemic form and evaluated against TryR in order to determine the key features of I that are associated with time-dependent inhibition. Kinetic data are consistent with an inactivation mechanism involving a conjugate addition of an active site cysteine residue onto the C-24-C-25 double bond of the tricyclic nucleus of 1. Comparison of data for synthetic (+/-)-1, the natural product, and other derivatives 7-10 from L. biennis confirms the importance of the unique structure of the tricyclic core as a motif for inhibitor design and reveals that the non-natural enantiomer may be a more suitable scaffold upon which thiophilic groups may be presented. (c) 2005 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)2266-2278
Number of pages13
JournalBioorganic & Medicinal Chemistry
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Apr 2006

Keywords

  • Disulfide reductase
  • Conjugate addition
  • Time-dependent inhibitors
  • Natural products

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