Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29

EM M. Kosower, AE E. Radkowsky, AH H. Fairlamb, SL L. Croft, RA A. Neal

Research output: Contribution to journalArticlepeer-review

Abstract

Tricyclic esters derived from bimanes have been synthesized with ring sizes near or equal to that of trypanothione disulfide (T(S)2), a bis-glutathionylspermidine that is involved in regulating the thiol status of Leishmania and other trypanosomatids. Modest activity for many of the compounds against Leishmania donovani with a maximum at the T(S)2 ring size suggests that the esters act as T(S)2 surrogates. However, no inhibition of T(S)2-reductase is observed for a number of the compounds. A series of tricyclic bimane amides with structures more closely analogous to T(S)2 are inactive in biological tests. New approaches were developed for the synthesis of the amides. The surprising effectiveness of the cyclic ester synthesis is explained. Acid chloride formation catalyzed by sulfides is briefly described.

Original languageEnglish
Pages (from-to)659-671
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume30
Issue number9
DOIs
StatePublished - 1995

Keywords

  • DFMO
  • GSH
  • GSSG
  • T(S)
  • T(SH)
  • acid chloride formation
  • antitrypanosomal drug
  • bimane ester
  • dl-α-difluoromethylornithine
  • glutathione
  • glutathione disulfide
  • reduced trypanothione
  • sulfide catalysis
  • trypanothione
  • trypanothione stereologue

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