Design,Synthesis Of Ferulic Acid Derivatives As Multitarget Directed Ligands For AD Therapy

Alzheimer’s disease (AD), the most common form of dementia in elderly people, is a progressive neurodegenerative disorder characterized by loss of cognitive ability, severe behavioral abnormalities, and ultimately death. Its pathogenesis is complex and its etiology is not still completely known, Current therapeutic options for the treatment of AD focuses on cholinesterases inhibitors and N-methyl-D-aspartate receptor antagonist, both of which can only be used to alleviate the symptoms of AD, and do not reverse or heal the disease. Therefore, it is particularly urgent to develop new anti-Alzheimer agents.Due to the complex pathological of AD, a single target can not prevent the progressive of neurodegeneration, multitarget-directed ligands design strategy had becomed a new direction in the research of anti-Alzheimer agents. In this article, we designed and synthesized three series of hybrids based on the multitarget-directed ligands design strategy, ferulic acid-memoquin hybrids (TM-Ⅰ), Ferulic acid -donepezil hybrids (TM-Ⅱ), Ferulic acid-O-alkyl amine derivatives (TM-Ⅲ).The synthesis of target compounds were accomplished by useing the general pathway. For the synthesis of TM-Ⅰ, Diamines were prepared by Gabriel reaction. Subsequently, ferulic acid with diamines in the presence of EDCI and HOBT afforded target compounds. Compounds TM-Ⅱ were prepared by direct reaction of ferulic acid with the corresponding secondary amine in the presence of EDCI and HOBT. For the synthesis of TM-Ⅲ, TM-Ⅱ-5 was reacted with dibromoalkanes which then reacted with corresponding secondary amine to give the target compounds.In this thesis,35 intermediates and 36 target compounds were synthesized. The structures of target compounds were determined by 1HNMR, some of them were further confirmed by 13C NMR and MS. Moreover, the solid compounds’ melting poin were determined.In this paper, The ChE inhibitory activity of target compounds were tested. The results showed that compounds TM-Ⅰ, TM-Ⅱ and TM-Ⅲ had cholinesterase inhibitory activity. TM-Ⅰ compounds showed better AChE inhibition activity, especially TM-Ⅰ-12 displayed the highest potency to Ee AChE with IC50 of 3.2μM, the enzyme kinetic study suggested that compound TM-Ⅰ-12 showed a mixed-type inhibition, binding to both CAS and PAS of AChE, TM-Ⅰ was a selective AChE inhibitors and a potential multi-targets lead compounds for the treatment of mild AD TM-Ⅱ exhibited good BuChE inhibition activity, Among them, TM-Ⅱ-5 displayed the highest potency to Eq BuChE with IC50 of 5.7 μM, what a pity TM-Ⅱ almost had no BuChE inhibitory activity. Based on TM-Ⅰ and TM-Ⅱ, we found that TM-Ⅲ had AChE and BuChE inhibitory activity. TM-Ⅲ were a selective BuChE inhibitors, especially, TM-Ⅲ-6 showed the strongest BuChE inhibition activity with IC50 of 0.021 μM, selective index was 101. It may be a potential multi-targets compound for the treatment of moderate-severe ADTo evaluate the effects of TM-Ⅰ, TM-Ⅱ and TM-Ⅲ against self-mediated A/β1-42 aggregation, we performed two individual studies:inhibitory activity and disaggregation potency on self-induced Aβ1-42 aggregation. the results showed that all the target compounds had moderate inhibitory activities.The antioxidant activities of the target compounds were tested by ORAC-FL method, the results showed that TM-Ⅰand TM-Ⅱ had good ability to remove free radicals, but TM-Ⅲ had low antioxidant activity, it is possible that the structure of phenolic hydroxyl are blocked. The neuroprotective capacity of TM-Ⅰ-12 and TM-Ⅲ-6 against oxidative stress was assayed, preliminary results showed that target compounds could capture the hydroxyl radical, generated by H2O2.To examine the cytotoxicity of the representative compound TM-Ⅲ-6, the cell viability was tested by MTT assays. The results showed that the therapeutic index is wide. The parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) was performed. The result showed that TM-Ⅲ-6 with permeability above 18.44 × 10-6 cm/s and could cross the BBB in vitro and reach theirbiological targets located in the CNS.As described above, TM-Ⅰ-12 was a potential multi-targets compound for the treatment of mild AD and TM-Ⅲ-6 was a potential multi-targets compound for the treatment of moderate-severe AD. in this thesis. This research has provided a good foundation for the development of novel multi-targets-directed anti-Alzheimer’s drugs.