Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer’s disease agents

• Published in: European journal of medicinal chemistry Vol. 187; pp. 111913 - 111931
• Main Authors: Yang, Gui-Xiang, Huang, Yan, Zheng, Lu-Lu, Zhang, Li, Su, Lin, Wu, Yu-Hang, Li, Jie, Zhou, Li-Cheng, Huang, Jin, Tang, Yun, Wang, Rui, Ma, Lei
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.02.2020; Elsevier
• Subjects: Aging - drug effects; Aging - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Animals; Anti-Aβ activity; Anti-inflammatory; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antioxidant; Astrocytes - drug effects; Astrocytes - metabolism; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Diosgenin; Diosgenin - chemical synthesis; Diosgenin - chemistry; Diosgenin - pharmacology; Dose-Response Relationship, Drug; Drug Design; Galactose - administration & dosage; Galactose - pharmacology; Humans; Inflammation - drug therapy; Inflammation - metabolism; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred ICR; Molecular Structure; Multi-target-directed ligands; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Pharmacology & Pharmacy; Protein Aggregates - drug effects; Science & Technology; Structure-Activity Relationship; Diosgenin; Multi-target-directed ligands; Alzheimer’s disease; Anti-Aβ activity; Antioxidant; Anti-inflammatory; Anti-A beta activity; OXIDATIVE STRESS; COGNITIVE IMPAIRMENT; DISCOVERY; SARSASAPOGENIN DERIVATIVES; POTENT; NEUROINFLAMMATION; BIOLOGICAL EVALUATION; Alzheimer's disease
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111913

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aβ activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 μM) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 μM) or Aβ (astrocytes protection = 70.2 ± 6.5%, 10 μM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aβ42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1β, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aβ activities. [Display omitted] •Design and synthesis of diosgenin carbamate derivatives.•Biological evaluation and structure-activity relationships of these compounds.•Binding between M15 to nNOS, Aβ42 and pro-inflammatory proteins predicted by molecular docking.•M15 possesses antioxidant, anti-inflammatory and anti-Aβ toxicity activities.•M15 is a potential multifunctional neuroprotective agent.