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

The primary objective of this study was to investigate the structure-activity relationship of a new series of 5F-like Aldose Reductase Inhibitors (ARIs) using in silico docking method. In this perspective, 6 novel ARIs have been designed and synthesized. Evaluation of the inhibition of these compounds to ALR2 was carried on with epalrestat and 5F as the references. It was found that the spacer of 5F-like ARIs has a great influence on their inhibitory activity. Rigid spacer with length equal to 3 âˆ¼ 4 carbon alkyl chain brings about better inhibitory activity. Among them, compound 4b was verified as the most active ARIs, where its IC50 value was 16.8 ± 1.3 nM. Furthermore, in silico docking studies using AutoDock 4.2 as well as molecular simulation using GROMACS 2022.1 showed that 5F-like ARIs adopt a dual-occupation mode. The interaction energy (-25 to -74 kcal/mol), as well as MM-GBSA binding free energy (-37 to -65 kcal/mol) was positively correlated with their ALR2 inhibition constant (2000 to 16.8 nM). Docking interaction explained well the structure-activity relationship. A pharmacophore model has been set up for 5F-like ARIs thereafter. This model indicates that as an effective ARI, the entity should have four characteristics: an aromatic center, two hydrogen bond donors, and one hydrogen bond acceptor. By the way, all the 5F-like ARIs reported here are good to mild antioxidant with EC50 value between 13.6 ± 1.2 and 71.1 ± 3.2 µM. All our data direct the further development of more optimal ARIs for the treatment of diabetic complication in the future.

Enhanced antioxidation capacity endowed to a mixed type aldose reductase inhibitor leads to a promising anti-diabetic complications agent.

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.