2. Academic Validation
  3. Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer's disease agents

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

  • Eur J Med Chem. 2020 Feb 1;187:111913. doi: 10.1016/j.ejmech.2019.111913.
Gui-Xiang Yang 1,  Yan Huang 1,  Lu-Lu Zheng 1,  Li Zhang 1,  Lin Su 1,  Yu-Hang Wu 1,  Jie Li 1,  Li-Cheng Zhou 1,  Jin Huang 1,  Yun Tang 2,  Rui Wang 3,  Lei Ma 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
  • 2 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. Electronic address: ytang234@ecust.edu.cn.
  • 3 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. Electronic address: ruiwang@ecust.edu.cn.
  • 4 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. Electronic address: malei@ecust.edu.cn.
PMID: 31837501 DOI: 10.1016/j.ejmech.2019.111913
Abstract

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.

Keywords

Alzheimer’s disease; Anti-Aβ activity; Anti-inflammatory; Antioxidant; Diosgenin; Multi-target-directed ligands.

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