Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents

• Published in: Bioorganic & medicinal chemistry letters 2021-07, Vol.43, p.128092, Article 128092
• Main Authors: Huang, Yi, Huang, Weiwei, Yang, Guixiang, Wang, Rui, Ma, Lei
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Diosgenin-triazole hybrids; Inflammation; Neuroprotective activities
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128092

[Display omitted] •The A ring of diosgenin was aromatized into a new type of skeleton structure.•A series of new synthetic diosgenin derivatives incorporating triazole were prepared.•Most compounds showed moderate to excellent in vitro activity against OGD induced neurotoxicity and LPS-induced NO production.•Compound L6 showed better activities and provided novel method to investigate diosgenin as neuroprotective agents. Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer’s disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.