Mesoionic pyridazine ribonucleosides. A novel biologically active nucleoside metabolite.

Abstract

4-Cyano-3-oxido-1-beta-D-ribofuranosylpyridazinium (10a) has been prepared from 4-cyano-3(2H)-pyridazinone (4) by using a low-temperature, kinetically controlled, silyl Hilbert-Johnson reaction followed by deblocking of the resulting triacetate derivative, 8a, with NaHCO3 in methanol. 10a is apparently the first example of a mesoionic analogue of a pyrimidine nucleoside. It was discovered as a urine metabolite of 4-cyano-3(2H)-pyridazinone (4) in mice. 10a possesses Gram-negative antibacterial activity in vivo against a systemic Escherichia coli infection in mice with an ED50 of 25-50 mg/kg. A series of 4-substituted 3-oxidopyridazinium ribonucleosides, 11a-h, were synthesized as analogues of 10a. 4-Chloro-3-oxido-1-beta-D-ribofuranosylpyridazinium (11a) was found to be several times more active than 10a against E. coli in vitro although it showed no in vivo activity.