Length and rigidity of the spacer impact on aldose reductase inhibition of the 5F-like ARIs in a dual-occupied mode

•A new series of 5F-like ARIs with molecular diversity has been designed and synthesized. 4b was the best ARI.•The inhibition to ALR2 is closely correlated with the length and rigidity of the spacer.•5F-like ARIs adopt dual-occupied binding mode to ALR2.•Docking studies and molecular simulation well explore the structure–activity relationship.•Pharmacophore model has been set up for 5F-type ARI.