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

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-Aß 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 Aß (astrocytes protection = 70.2 ± 6.5%, 10 µM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aß42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1ß, 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-Aß activities.