Synthesis of natural flutimide and analogous fully substituted pyrazine-2,6-diones, endonuclease inhibitors of influenza virus.
Flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione, is a fungal metabolite isolated from a new species of Delitschia cofertaspora. It has been shown to selectively inhibit cap-dependent endonuclease activity of influenza virus A. The inhibition of this activity is a target for the potential development of a therapeutic agent to treat influenza infections. A convergent total synthesis of flutimide starting from L-leucine has been described. The synthetic methodology has been extended to include the synthesis of specifically designed aromatic analogues of flutimide, some of which exhibited greater than 7-fold improvement in activity. The most potent compounds were those with p-fluorobenzylidene or p-methoxybenzylidene substitutions at C-5 of 3H-pyrazine-2,6-dione and showed IC(50) values of 0.9 and 0.8 microM, respectively. The details of the rationale for the synthetic design, syntheses, and biological activities of these analogues are described.
Singh
S B
SB
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
Tomassini
J E
JE
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004720:Endonucleases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D010879:Piperazines; D011719:Pyrazines; C101423:flutimide; D004720:Endonucleases