Sugar-derived di- and tetrahydropyridazinones: Synthesis of new glycosidase inhibitors

The N-unsubstituted D-arabino-tetrahydropyridazinone 7 is a micromolar inhibitor of beta-glucosidases from sweet almonds (competitive), Caldocellum saccharolyticum (mixed), yeast alpha-glucosidase (competitive), jack bean alpha-mannosidase (competitive), and snail beta-mannosidase (competitive). The N-substituted tetrahydropyridazinones 22, 24, and 26 are weak inhibitors of these glycosidases, and so are the dihydropyridazinones 8 and 17-19, where the best inhibition was observed for 8 (K-i = 56 mu M for jack bean alpha-mannosidase). The tetrahydropyridazinones were obtained by reduction of the corresponding dihydropyridazinones with NaCNBH3, and the dihydropyridazinones were prepared by treatment with hydrazine or substituted hydrazines of the known and readily available D-threo-pent-2-uluronate 11.