Compound with dual restraining activities to acetyl cholinesterase and butyryl cholinesterase and use thereof

Abstract

The invention adopts a virtual medicine screening technology and a high-throughput screening technology, assesses the AChE inhibitory activity of more than ten thousand samples in a compound sample library and finds a batch of compounds with higher inhibitory activity by establishing a virtual acetylcholinesterase inhibitor screening method and an AChE activity detection method. Then according to the pathological features of senile dementia, the compounds with higher AChE inhibitory activity are subject to butyryl choline esterase inhibitory activity detection. Research results show that bimolecular 3-piperidyl-ethyl phenyl ketone not only has comparatively high AChE inhibitory activity, but also has very strong BuChE inhibitory activity; the results of animal experiments prove that the bimolecular 3-piperidyl-ethyl phenyl ketone can remarkably improve aphronesia caused by scopolamine and sodium nitrite and can enhance the ability of learning and memory.

Description

technical field

[0001] The invention relates to a class of bimolecular 3-piperidinyl-propiophenone compounds, which not only have strong AChE inhibitory activity, but also have strong BuChE inhibitory activity; The application in dementia belongs to the technical field of medicine. Background technique

[0002] Alzheimer's is closely related to aging. As the world population ages, so does the incidence of dementia. According to statistics, the annual incidence rate of the elderly aged 65-69 is 1.4‰, that of 70-74 years old is 3.9‰, that of 75-79 years old is 16.7‰, and that it increases to 45.4‰ at the age of 85. Alzheimer's is a disease that seriously affects the quality of life and health of the elderly after heart disease, tumors, and diabetes. This disease can damage memory and decrease the ability of daily life. Its gradually declining functions include: (1) memory and cognitive function-showing memory decline, often forgetting the names of relatives and friends incl...

Examples

Embodiment 1

[0049] Example 1: Virtual screening of AchE inhibitors. Based on the crystal structures of the two complexes of donepezil and huperzine A with AChE, the virtual screening program FlexX and the consistent scoring method were used to add the results of the two virtual screenings, and a total of 2855 compounds were selected with higher scores. as the test compound. The prediction results were analyzed comprehensively, and some compounds were selected for activity detection.

Embodiment 2

[0050] Example 2: Inhibitory activity on AchE.

[0051] According to the literature, the AchE inhibitor screening model was established, and the activity of the selected 2885 compounds was tested. It was found that compound 1, compound 2, compound 3, and compound 4 had high AChE inhibitory activity. The activity values ​​are shown in Table 1. its IC 50 1 μM to 10 μM.

[0052] AChE Inhibitory Activity of Compounds in Table 1 in Vitro

[0053]

[0054] Note: The above data is the average value of 3 experimental data.

Embodiment 3

[0055] Example 3: Inhibitory activity against butyrylcholinesterase

[0056] Establish a butyrylcholinesterase (Butyrocholinesterase, BChE) inhibitor screening model according to the literature, and use this model to detect the activity of the compound,

[0057] The experimental results show that compounds (1), (2), (3) and (4) have strong BChE inhibitory activity, and the activity values ​​are shown in Table 2. its IC 50 0.1 μM to 1 μM. The positive control drug huperzine A has no inhibitory activity on BChE, and the positive drug donepezil (donepezil) has lower inhibitory activity on BChE than the active compounds (1), (2), (3) and (4).

[0058] BChE Inhibitory Activity of Compounds in Table 2

[0059]

[0060] Note: The above data are the average value of 3 experimental data.

technical field

[0001] The invention relates to a class of bimolecular 3-piperidinyl-propiophenone compounds, which not only have strong AChE inhibitory activity, but also have strong BuChE inhibitory activity; The application in dementia belongs to the technical field of medicine. Background technique

[0002] Alzheimer's is closely related to aging. As the world population ages, so does the incidence of dementia. According to statistics, the annual incidence rate of the elderly aged 65-69 is 1.4‰, that of 70-74 years old is 3.9‰, that of 75-79 years old is 16.7‰, and that it increases to 45.4‰ at the age of 85. Alzheimer's is a disease that seriously affects the quality of life and health of the elderly after heart disease, tumors, and diabetes. This disease can damage memory and decrease the ability of daily life. Its gradually declining functions include: (1) memory and cognitive function-showing memory decline, often forgetting the names of relatives and friends incl...

Examples

Embodiment 1

[0049] Example 1: Virtual screening of AchE inhibitors. Based on the crystal structures of the two complexes of donepezil and huperzine A with AChE, the virtual screening program FlexX and the consistent scoring method were used to add the results of the two virtual screenings, and a total of 2855 compounds were selected with higher scores. as the test compound. The prediction results were analyzed comprehensively, and some compounds were selected for activity detection.

Embodiment 2

[0050] Example 2: Inhibitory activity on AchE.

[0051] According to the literature, the AchE inhibitor screening model was established, and the activity of the selected 2885 compounds was tested. It was found that compound 1, compound 2, compound 3, and compound 4 had high AChE inhibitory activity. The activity values ​​are shown in Table 1. its IC 50 1 μM to 10 μM.

[0052] AChE Inhibitory Activity of Compounds in Table 1 in Vitro

[0053]

[0054] Note: The above data is the average value of 3 experimental data.

Embodiment 3

[0055] Example 3: Inhibitory activity against butyrylcholinesterase

[0056] Establish a butyrylcholinesterase (Butyrocholinesterase, BChE) inhibitor screening model according to the literature, and use this model to detect the activity of the compound,

[0057] The experimental results show that compounds (1), (2), (3) and (4) have strong BChE inhibitory activity, and the activity values ​​are shown in Table 2. its IC 50 0.1 μM to 1 μM. The positive control drug huperzine A has no inhibitory activity on BChE, and the positive drug donepezil (donepezil) has lower inhibitory activity on BChE than the active compounds (1), (2), (3) and (4).

[0058] BChE Inhibitory Activity of Compounds in Table 2

[0059]

[0060] Note: The above data are the average value of 3 experimental data.

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