Abstract
Recent studies have suggested that aldose reductase inhibition preferentially inhibits the growth of cancer cells. However, the investigations of this issue are not many. Novel nine substituted- 4'-iminospiro[indoline-3,3'-[1,2,5] thiadiazolidinyl]-2-one 1',1'-dioxide derivatives were designed by both isosteric replacement of the imidazolidine-2,5-dione moiety in spirohydantoin scaffold and conformational rigidification approaches. A QSAR with high predictive power (r(2) = 0.99) was created from a series of potent aldose reductase inhibitors and was used to predict the activity of our new compounds. Compound 5 showed the best docking score (- 33.24 kcal/mol) with the least RMSD value (< 1.5) obtained by molecular dynamic simulations over 20 ns. All compounds showed promising anticancer activities especially compound 5 that achieved the highest inhibitory activities with IC(50); 0.013, 0.031, 0.064, and 0.048 mmol/L against breast, colon, prostate, and lung cell lines respectively. The discovery of this lead compound confirmed the rational design. Further investigations may be required for optimization of this compound.