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Synthesis of novel tetrahydroisoquinoline class acetylcholine inhibitors virtual screening and key intermediates

Author: MaGuanJun
Tutor: JiangYuRen
School: Central South University
Course: Pharmaceutical Engineering
Keywords: corydaline acetylcholinesterase inhibitor molecular docking
CLC: TQ464.8
Type: Master's thesis
Year: 2011
Downloads: 75
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Abstract


Alzheimer’s disease (AD), the most common form of neurodegenerative senile dementia, and it is characterized by loss of memory and progressive impairment in cognitive functions. Widespread epidemic, long-term treatment and high medical costs has made AD as a major public health problem. On the basis ofβ-amyloid peptide hypothesis, the accumulation of theβ-amyloid peptide (Aβ) in the brain has been thought to be a key factor in the pathogenesis of the disease. The major marketed drugs for the symptomatic treatment of AD are acetylcholinesterase (AChE) inhibitors which inhibit AChE activity to promote an increase in the concentration and the duration of synaptic acetylcholine in the brain. Recently the peripheral anionic sites (PAS) of AChE has been indicated to be involved in A(3 peptide aggregation and formed a steady compound with Aβ. Thus, AChE inhibitors, which may alleviate cognitive deficits and behave as disease-modifying agents by inhibiting theβ-amyloid (AP) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Such AChE inhibitors are becoming a new field for AD therapy.The lead compound Corydaline is a type of cordalis alkaloid. Molecular docking method (GOLD) was introduced to investigate the binding mode of corydaline at TcAChE and screen a series of tetrahydroisoquinoline derivatives. Molecular modeling obtained by GOLD suggests that the phenyl group A of the derivatives buried within the core of the enzyme binds with the catalytic site via face-to-faceπ-stacking interaction (distance:3.155A) with Trp84. The phenyl group B reaches the peripheral site on the surface of the enzyme by face-to-faceπ-stacking interaction (distance:3.225 A) with Trp279.The protonated nitrogen atom of the tetrahydroisoquinoline moiety interacts with the phenyl group of Phe330 by cation-7r interaction (distance:4.021 A). The phenyl group of the tetrahydroisoquinoline moiety interacts with Tyr334 by a classic parallelπ-πaccumulation (distance:3.818 A).Pharmacokinetics and metabolic toxicity of 10 tetrahydroisoquin-oline derivatives which got high fitness score was predicted by Pallas 3.5. All the compounds possess better pharmacokinetic characteristics, and the toxicities do not increase compared to lead compound. Thus all the compounds investigated show good potential pharmacokinetics and less metabolic toxicity. The final results give us some useful indications for the treatment of AD.In this thesis,4 Compounds were totally synthesized used 3, 4-dimethoxyl- benzaldehyde as starting reagent. The whole synthesis steps include substitution with benzylbromide, condensation with nitromethane, nucleophilic addition with sodium methoxide, reduction with LiAlH4. The structures of the compounds were confirmed by 1HNMR, IR.

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