Mesoionic pyridazine ribonucleosides. A novel biologically active nucleoside metabolite.
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.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy; D006090:Gram-Negative Bacteria / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013552:Swine
D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D011724:Pyridazines; D012263:Ribonucleosides