新型α1受体拮抗剂先导化合物的寻找：2-[4-(芳氧烷基)哌嗪-1-基]苯并噁唑的合成、生物活性及3D-QSAR研究  

Searching for Novel Lead Compounds of α_1-AR Antagonists:Synthesis,Bioassays and 3D-QSAR of 2-[4-(Aryloxyalkyl)-piperazin-1-yl]benzo[d]oxazole Compounds

作　　者：李嘉宾[1] 刘海春[1] 张立[2] 王涛[3] 江振洲[3] 夏霖[4] 

机构地区：[1]中国药科大学无机化学教研室,南京210009 [2]中国科学院上海有机化学研究所上海质谱中心,上海200032 [3]中国药科大学新药筛选中心,南京210009 [4]中国药科大学药物化学教研室,南京210009

出　　处：《高等学校化学学报》2009年第5期903-907,共5页Chemical Journal of Chinese Universities

基　　金：国家“八六三”计划(批准号:2002AA2Z3118)资助

摘　　要：为寻找用于治疗良性前列腺增生的新型α1受体拮抗剂,以2-({4-[2-(2-氯苯氧基)乙基]哌嗪-1-基}甲基)-5-甲基苯并噁唑(wb5c)为先导物,以5-氯-2-氨基酚和取代苯酚为原料,经缩合、卤代、氨化、William-son醚合成、取代等反应,设计合成了8个新化合物,其结构经ESI-MS,1HNMR,IR及HRMS确证.大鼠肛尾肌收缩功能实验表明,目标化合物具有中等强度α1受体拮抗活性.结合前期工作,以18个2-[4-(芳氧烷基)哌嗪-1-基]苯并噁唑类化合物及其生物活性为样本,运用Sybyl软件建立了该类化合物α1-AR拮抗活性的CoMFA模型,q2=0.430,R2=0.907,立体场与静电场的贡献分别为46.5%和53.5%,此模型为进一步结构优化提供了有益信息.Benign prostatic hyperplasia（BPH） is a pathological disorder in the aged men that causes voiding difficulties and thus impacts the quality of life. α1-AR antagonists are clinically used for the treatment of BPH. Aimed at searching for the novel α1-adrenoceptor antagonists, eight target compounds bearing 2-（ piperazin-1-yl）benzo[ d] oxazole scaffold were designed from our lead compound wb5c and synthesized from 5-chloro-2- aminophenol and substituted phenols via condensation, chloration and amination, Williamson ether synthesis and substitution etc.. All target compounds were identified by ESI-MS, IR, ^1H NMR and HRMS. Functional bioassays showed that they had moderate antagonistic activities against α1 -AR. The CoMFA model was constructed for 2- （piperazin-1-yl） benzo[ d ] oxazole derivertives via SYBYL software package, q^2 = 0. 430, r^2 = 0. 907, fractions of steric and electrostatic fields were 0. 465 and 0. 535, respectively. 3D-QSAR analysis leads to insight into further structural optimization.

关 键 词：良性前列腺增生 Α1受体 拮抗剂 苯并噁唑 哌嗪 比较分子力场分析 

分 类 号：O626.24[理学—有机化学]