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

• Published in: Bioorganic chemistry Vol. 120; p. 105624
• Main Authors: Liu, Yuanlin, Mo, Hui, Zhang, Kun, Yin, Meili, Yuan, Sheng, Li, Yanbing, Li, Yifang, Zhu, Wenda, Fan, Yiping, Zeng, Yancong, Kurihara, Hiroshi, He, Rongrong, Chen, Heru
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.03.2022; Elsevier
• Subjects: Aldose reductase inhibitor; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Diabetic complications; Diabetic peripheral neuropathy; Drug design; Hyperglycemia; Life Sciences & Biomedicine; Mechanism-based antioxidant; Oxidative stress; Physical Sciences; Science & Technology; Oxidative stress; Hyperglycemia; Diabetic peripheral neuropathy; Mechanism-based antioxidant; Aldose reductase inhibitor; Diabetic complications; Drug design; RISK; MECHANISMS; MODEL; NEUROPATHY; DISEASE; GENE-EXPRESSION; STRESS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105624

[Display omitted] •The inhibition, selectivity and anti-DC of ARI are positively correlated with antioxidation capacity.•6d was the best ARI and antioxidant.•6d was a mixed type ARI.•6d were shown a more promising anti-DC. 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.