A series of 5f-based new compounds has been designed and synthesized. In vitro screening demonstrated that the binding affinity and selectivity on
aldose reductase (AR) were positively correlated with its antioxidation capacity. Compound 6d was verified the most active candidate, where its IC50, selective index (SI), and EC50 value was 22.3 ± 1.6 nM, 236.2, and 8.7 μM respectively. 6d was confirmed as both an excellent
antioxidant and
aldose reductase inhibitor (ARI). It was identified as a mixed type ARI with Ki and Kis values of 23.94 and 1.20 nM. When evaluated by a high-
glucose impaired chicken embryo model, it was found that 6d attenuated the incidence of
neural tube defect (NTD) and death rate in a dose-dependent manner. It significantly improved the
hyperglycemia-induced abnormalities of
body weight and morphology of chicken embryos. 6d reversed the
hyperglycemia-raised AR activity,
sorbitol accumulation,
reactive oxygen species (ROS) and
malondialdehyde (MDA) levels. It restored the high-
glucose-reduced Pax3
protein expression. At the same dose (0.5 μM), 6d showed better effects than 5f in all the above detections. By the way, 6d did not affect
hyperglycemia-elevated
aldehyde reductase (ALR1) activity. This evidence together with its kinetic properties, implicated that 6d is a high selective ARI without the suspicion of promiscuity. 6d was proved here an effective agent to treat diabetic
peripheral neuropathy (
DPN). Whether 6d has potential to treat other types of
diabetic complications (DC) needs to be further investigation.