Design And Biological Evaluation Of Three-target Ligands For Treatment Of Vascular Dementia Disease

Vascular Dementia (VD) is defined as a loss of cognitive function resulting from ischemic or hemorrhagic brain lesions due to various cerebral vascular diseases. With the acceleration of aging society, China has become the largest country in the number of elderly population all over the world. The prevalence of VD has reached 1.1～3.0% in elderly people over the age of 65 years, and the trend is still rising year by year. As the major complication of cerebrovascular disease, VD severely threaten physical health and life quality of the patients. It also bring a heavy burden of the society and family, which has got much attention these years.Duo to the complicated pathogenesis, the therapy of VD is usually aimed at three targets:anti-platelet aggregation; anti-acetylcholinesterase (AChE) and neuron protection. The therapy of anti-platelet aggregation can increase blood flow and improve cerebral oxygen in brain; anti- AChE and protection of neurons can improve the function of cognition. Nowadays, numerous medications were used to treat VD, but the curative effect is not so good for the reason of single-target drug of these medicines, especially for the serious patients. So combination of the drugs is normally used in clinical treatment, but it has the risk interactions with other medication, bioavailability, pharmacokinetics, toxicity, etc. So it is necessary to develop new multiple-targets drugs for the treatment of VD.According to the theory of Traditional Chinese Medicine and a variety of clinical reports, some natural medicines can increase blood flow, improve cerebral oxygen in brain and protect neurons, but without the effect for anti-AChE. In this study, paeonol and ligustrazine as lead compounds were modified to synthesis novel three-targets drugs for the treatment of VD. The results are listed as follows:1. Ten novel AChE inhibitions were firstly synthesized through rational drug design and structure-based virtual screeningBy using paeonol and ligustrazine as lead compounds,92 AChE inhibitions were designed. To predict the AChE inhibitory activities of these compounds, three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on 90 AChE inhibitions with known AChE inhibitions abilities. The comparative field analysis (CoMFA) model with CoMFA descriptors as variables and the half maximal inhibitory concentration (pIC50) as the dependent variable. Statistical results indicate that this model has satisfactory residual values for the training set and test set and will be useful to predict the biological activity of the potential drugs. According to the CoMFA model, the inhibitory activities of 92 AChE inhibitions were predicted. Finally, ten new compounds were synthesized, which were predicted with great AChE inhibitory activity by using the 3D-QSAR CoMFA model.2. Compound 11 showed stronger biological activities for; and neuron protection.The synthesized 10 compounds were investigated by anti-AChE activity, anti-platelet aggregation activity and the ability of neuron protection. Biological assays revealed that compound 11 has strong AChE inhibition property, with IC50 values to sub-micromolar (IC50=0.24 μmol·L-1). It also showed potent inhibitory activity against platelet aggregation (in vitro). The inhibitory rate of blood platelet was 81.47%, administering at the dosage of 100 μmol·L-1, which better than aspirin (81.47%), paeonol (51.68%) and ligustrazine (72.80%). It also could significantly inhibit hydrogen peroxide-induced neuronal PC 12 cell death assessed by MTT assay. In the concentration range of 40 μM, the proliferation rate of PC 12 cell was 85.24%, which better than paeonol (61.45%) and ligustrazine (67.29%).3. The biological activities for; and neuron protection of compound 11 were futher confirmed by animal experiments.Model of Vascular Dementia in rats were induced by ligating bilateralcommon carotid artery (2-VO).The therapy effect of compound 11 was evaluated the morphological changes of CA1 hippocampal area, the content changes of ACh adn MDA, the activities of AChE and SOD, and the activity of anti-platelet aggregative. The results shown that the learning and memory abilities of VD model rats could significant improved by treating compound 11. It had inhibitory activity against platelet aggregation and neuroprotective effects on the area of hippocampal CA1. Further experiments proved that it could significantly enhance the activities of AChE and SOD, reduce the content of ACh adn MDA. Compare to positive control group (Donepezil), compound 11 has advantage for multi-targets.