New neplanocin analogues. 12. Alternative synthesis and antimalarial effect of (6'R)-6'-C-methylneplanocin A, a potent AdoHcy hydrolase inhibitor

J Med Chem. 2002 Jan 31;45(3):748-51. doi: 10.1021/jm010374i.

Abstract

An improved method for the synthesis of (6'R)-6'-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl(3) to the neplanocin A 6'-aldehyde derivative 6. Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. The antimalarial EC(50) value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC(50) = 1.8 mg/kg/day).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemical synthesis*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Adenosylhomocysteinase
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hydrolases / antagonists & inhibitors*
  • Malaria / drug therapy
  • Mice
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • 6'-C-methylneplanocin A
  • Hydrolases
  • Adenosylhomocysteinase
  • Adenosine