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

摘要

In order to produce an effective 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-A beta activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 +/- 2.2%,10 mu M) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 +/- 3.4%, 10 mu M) or AO (astrocytes protection = 70.2 +/- 6.5%, 10 mu M). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, A beta(42) and pro-inflammatory proteins. Western blot demonstrated that MIS decreased IL-beta, IL-6 and TNF-alpha level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-inducedROS 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-All activities. (C) 2019 Elsevier Masson SAS. All rights reserved.