New Neplanocin Analogues. 12. Alternative Synthesis and Antimalarial Effect of (6‘R)-6‘-C-Methylneplanocin A, a Potent AdoHcy Hydrolase Inhibitor

• Published in: Journal of medicinal chemistry 2002-01, Vol.45 (3), p.748-751
• Main Authors: Shuto, Satoshi, Minakawa, Noriaki, Niizuma, Satoshi, Kim, Hye-Sook, Wataya, Yusuke, Matsuda, Akira
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Adenosylhomocysteinase; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hydrolases - antagonists & inhibitors; Malaria - drug therapy; Medical sciences; Mice; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010374i

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 MeTiCl3 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 EC50 value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (EC50 = 1.8 mg/kg/day).