噻唑并[3，2-a]嘧啶类化合物的设计、合成及生物活性研究
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摘要
老年性痴呆(简称AD,1907年由Alofs Alzheimer医生发现)为中枢神经系统的一种退行性病变,是一种渐次性疾病,即病人在患病初期症状较轻微,慢慢地各种症状会越来越严重,直至丧失处理日常行为的能力。AD患者的认知功能明显减退,且伴有严重的行为异常,如:易怒、焦虑、沮丧、不辩方向、不安等。病理学研究表明,AD患者脑内胆碱能神经系统发生退行性改变,增加脑内乙酰胆碱水平可改善AD患者的症状。
乙酰胆碱酯酶(AChE)是与突触体相关联的一种蛋白酶,可促进神经递质乙酰胆碱(ACh)在胆碱能突触体中水解并释放出胆碱。因此,乙酰胆碱酯酶已成为设计与机理相关的抑制剂的目标酶。
根据虚拟筛选结果,我们设计并合成了23个5H-噻唑并[3,2-a]嘧啶类化合物,其中20个化合物未见报道。经核磁共振氢谱、质谱、红外光谱确定了目标化合物组成和结构。
参考Ellman法,以氢溴酸新斯的明为阳性对照药,对目标化合物进行了抑制乙酰胆碱酯酶活性的体外筛选。实验结果表明,化合物7-甲基-5-丙基-3-(4-羟基苯基)-5H-噻哗并[3,2-a]嘧啶-6-羧酸乙酯(CLM02)、7-甲基-3-(4-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM06)、7-甲基-3-(2-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM10)、6-乙酰基-7-甲基-3-(4-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶(CLM15)对乙酰胆碱酯酶有显著的抑制作用。化合物7-甲基-5-丙基-3-(4-氯苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM03)、7-甲基-3-(4-甲氧基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM07)、7-甲基-3-(2-羟基苯基)-5-苯基-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM12)、7-甲基-3-[4-(2-二甲氨基)乙氧基苯基]-5-甲氧基苯基-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM22)对乙酰胆碱酯酶具有抑制作用。根据药理筛选实验结果,初步总结了目标化合物抑制乙酰胆碱酯酶活性的构效关系。
Alzheimer's Disease,discovered by Dr.Alois Alzheimer in1907,is described as a degenerative of the central nervous system(CNS).AD is a progressive disease,i.e.the onset of the disease may show mild symptoms,but these symptoms will sooner or later become more and more severe until the patient loses his or her capacity to handle normal daily activities.AD patients exhibit marked decline in cognitive ability and severe behavioral abnormalities such as irritability,anxiety, depression,disorientation and restlessness.Pathology study found that cholinergic system had a retrogression change in the brain of AD patients,and the AD patients' symptom could be improved when the concentration of ACh was increased.
Acetylcholinesterase is an enzyme projecting into the synapse.It promotes the hydrolysis of the neurotransmitter acetylcholine at the cholinergic synapses with liberation of choline.Because of its central role in the neurotransmission system,the AChE has been attractive target for the rational design of mechanism-based inhibitors. According to the results of virtual screen,5H-thiazolo[3,2-a]pyrimidine derivatives were designed as acetylcholineterase inhibitor.23 target compounds were synthesized and characterized by ~1H-NMR,IR,GC-MS and LC-MS,among which 20 compounds were not yet reported in the literature.
According to the Ellman experiments,in comparison to the neostigmine bromide,the inhibitory acetylcholineterase activitivies of the target compounds was tested.Some of the target compounds such as ethyl 3-(4-hydroxyphenyl)-7-methyl-5-propyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (CLM02),ethyl 3-(4-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM06),ethyl 3-(2-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 10),3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-ethanone(CLM15)showed potent inhibitory activitivies on acetylcholineterase;ethyl 3-(4-chlorophenyl)-7-methyl-5-propyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM03),ethyl 3,5-bis(4-methoxyphenyl)-7- methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate(CLM07),ethyl 3-(2-hydroxyphenyl)-5-phenyl-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 12),ethyl 3-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM22)showed inhibitory activity against acetylcholineterase.
The structure and inhibitory activity relationship of target compounds were discussed.
乙酰胆碱酯酶(AChE)是与突触体相关联的一种蛋白酶,可促进神经递质乙酰胆碱(ACh)在胆碱能突触体中水解并释放出胆碱。因此,乙酰胆碱酯酶已成为设计与机理相关的抑制剂的目标酶。
根据虚拟筛选结果,我们设计并合成了23个5H-噻唑并[3,2-a]嘧啶类化合物,其中20个化合物未见报道。经核磁共振氢谱、质谱、红外光谱确定了目标化合物组成和结构。
参考Ellman法,以氢溴酸新斯的明为阳性对照药,对目标化合物进行了抑制乙酰胆碱酯酶活性的体外筛选。实验结果表明,化合物7-甲基-5-丙基-3-(4-羟基苯基)-5H-噻哗并[3,2-a]嘧啶-6-羧酸乙酯(CLM02)、7-甲基-3-(4-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM06)、7-甲基-3-(2-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM10)、6-乙酰基-7-甲基-3-(4-羟基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶(CLM15)对乙酰胆碱酯酶有显著的抑制作用。化合物7-甲基-5-丙基-3-(4-氯苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM03)、7-甲基-3-(4-甲氧基苯基)-5-(4-甲氧基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM07)、7-甲基-3-(2-羟基苯基)-5-苯基-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM12)、7-甲基-3-[4-(2-二甲氨基)乙氧基苯基]-5-甲氧基苯基-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯(CLM22)对乙酰胆碱酯酶具有抑制作用。根据药理筛选实验结果,初步总结了目标化合物抑制乙酰胆碱酯酶活性的构效关系。
Alzheimer's Disease,discovered by Dr.Alois Alzheimer in1907,is described as a degenerative of the central nervous system(CNS).AD is a progressive disease,i.e.the onset of the disease may show mild symptoms,but these symptoms will sooner or later become more and more severe until the patient loses his or her capacity to handle normal daily activities.AD patients exhibit marked decline in cognitive ability and severe behavioral abnormalities such as irritability,anxiety, depression,disorientation and restlessness.Pathology study found that cholinergic system had a retrogression change in the brain of AD patients,and the AD patients' symptom could be improved when the concentration of ACh was increased.
Acetylcholinesterase is an enzyme projecting into the synapse.It promotes the hydrolysis of the neurotransmitter acetylcholine at the cholinergic synapses with liberation of choline.Because of its central role in the neurotransmission system,the AChE has been attractive target for the rational design of mechanism-based inhibitors. According to the results of virtual screen,5H-thiazolo[3,2-a]pyrimidine derivatives were designed as acetylcholineterase inhibitor.23 target compounds were synthesized and characterized by ~1H-NMR,IR,GC-MS and LC-MS,among which 20 compounds were not yet reported in the literature.
According to the Ellman experiments,in comparison to the neostigmine bromide,the inhibitory acetylcholineterase activitivies of the target compounds was tested.Some of the target compounds such as ethyl 3-(4-hydroxyphenyl)-7-methyl-5-propyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (CLM02),ethyl 3-(4-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM06),ethyl 3-(2-hydroxyphenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 10),3-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-ethanone(CLM15)showed potent inhibitory activitivies on acetylcholineterase;ethyl 3-(4-chlorophenyl)-7-methyl-5-propyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM03),ethyl 3,5-bis(4-methoxyphenyl)-7- methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate(CLM07),ethyl 3-(2-hydroxyphenyl)-5-phenyl-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM 12),ethyl 3-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(4-methoxylphenyl)-7-methyl-5H-thiazolo [3,2-a]pyrimidine-6-carboxylate(CLM22)showed inhibitory activity against acetylcholineterase.
The structure and inhibitory activity relationship of target compounds were discussed.
引文
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