Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer’s disease

Abstract

Herein, a series of novel O -alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a , 5d , 5e , 5f , and 5h indicated significantly selective MAO-B inhibitory potency (IC 50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a , 5d , 5e , 5f , and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced A β 1-42 aggregation, and potent neuroprotective effect on A β 1-42 -induced PC12 cell injury. Furthermore, compounds 5a , 5d , 5e , 5f , and 5h presented good blood–brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [ 11 C] 5f demonstrated that [ 11 C] 5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.

Research progress of natural products and their derivatives against Alzheimer’s disease

“…Compounds 2 , 3 , 4 , 5 , and 6 exhibited significant selective MAO-B inhibition (IC 50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively), significantly inhibited Aβ1-42 aggregation, and effectively protected PC12 cells Aβ1-42-induced damage, all of which have a good blood-brain barrier permeability. This is consistent with the properties required for the development of new drugs 20 ( Figure 1 , Table 1 ).…”

Imaging of Tauopathies with PET Ligands: State of the Art and Future Outlook

“…An example is the paper of Zhu et al, in which a series of novel O-alkyl ferulamide derivatives were synthesized. Ferulic acid (FA) is a polyphenol particularly represented in maize bran that seems capable of potentiating the inhibition of monoamine oxidase B (MAO-B) if benzyl derivatives and alkyl fragments were introduced into its skeleton [45]. Monoamine oxidases A (MAO-A) and B are responsible for the degradation of neurotransmitters such as dopamine, serotonin, adrenaline, and noradrenaline.…”