Synthesis and aldose reductase inhibition activity of spiro-[9H-fluoren-9,4'-imidazolidine]-2,5'-dione derivatives

Abstract A series of substituted spiro-[9 H -fluoren-9,4′-imidazolidine]-2′,5′-diones was prepared by Bucherer—Berg condensation followed by various modifications of a carboxylic functional group. The compounds obtained were examined for their abilities to inhibit the enzyme aldose reductase both in vitro and in vivo . High potency in inhibiting the semi-purified calf lens enzyme in vitro was observed for several of the tested compounds. Two of the compounds have been found to be very effective in reducing sorbitol accumulation in the lenses and sciatic nerves of rats treated with streptozotocin. Substitution on positions 1 or 2 of the fluorene ring led to inactive compounds, whereas substitution on positions 3 or 4 enhanced inhibitory activity with respect to the unsubstituted spirofluorohydantoin 50 . These observations are discussed in light of the previously published structural requirements of the allosteric binding site of the enzyme aldose reductase.