Novel biologically active nonpeptidic inhibitors of myristoylCoA:protein N-myristoyltransferase

J Med Chem. 1998 Mar 12;41(6):996-1000. doi: 10.1021/jm980001q.

Abstract

A new class of biologically active nonpeptidic inhibitors of Candida albicans NMT has been synthesized starting from the octapeptide ALYASKLS-NH2 (2). The synthetic strategy entailed the preparation of novel protected Ser-Lys mimics 9 and 12 from (S)- or (R)-3-iodotyrosine and then grafting key enzyme recognition elements in a stepwise manner. Like 2, compounds 16, 17, and 18 are competitive Candida NMT inhibitors that bind to the peptide recognition site of the enzyme. Moreover, 16-18 have an affinity comparable to that of 2 even though they are devoid of peptide bonds. In contrast to 2, these nonpeptidic inhibitors exhibit antifungal activity.

Publication types

  • Comparative Study

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Antifungal Agents / chemical synthesis*
  • Antifungal Agents / pharmacology
  • Candida albicans / drug effects
  • Candida albicans / enzymology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Stereoisomerism

Substances

  • Antifungal Agents
  • Enzyme Inhibitors
  • Imidazoles
  • N-(1-((3-(aminobutyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine
  • N-(1-((3-(aminopropyl)-4-(cyclohexylethoxy)phenyl)methyl)-2-hydroxyethyl)-4-((2-methyl-1H-imidazol-1-yl)butyl)benzeneethanamine
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase