SYNTHESIS AND 5-LIPOXYGENASE INHIBITORY ACTIVITIES OF SOME NOVEL 2-SUBSTITUTED 5-BENZOFURAN HYDROXAMIC ACIDS

A series of 2-substituted benzofuran hydroxamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in, vitro and in vivo 5-lipoxygenase activity and found to b e potent inhibitors of the enzyme. Substituents which enhanced lipophi licity near the 2-position of the benzofuran nucleus increased inhibit or potency but reduced oral activity. Incorporation of small polar sub stituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most pote nt inhibitors of this series in vitro were 1-(2-phenyl-5-benzofuranyl) -ethyl]furancarboxamide (12) and methyl thoxyphenyl)-5-benzofuranyl]et hyl]-5-oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was -hydroxy-N-[1-(2-phenyl-5-benzofuranyl)e thyl]urea, 20, with an ED(50) = 10.3 mg/kg.