1-(1,4-苯并二噁烷-2-羰基)-4-取代芳氧烷基哌嗪类α1受体拮抗剂的合成、生物活性及3D-QSAR研究
Synthesis,biological evaluation and 3D-QSAR study of 1-(1,4-benzodioxan-2-ylcaronyl)-4-aryloxyalkyl-piperazines as α1-adrenoceptor antagonists
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摘要: 为寻找新的1,4-苯并二噁烷类α1受体拮抗剂，选取1,4-苯并二噁烷为母核，以儿茶酚和取代苯酚为原料，分别经关环、水解、成酰胺、取代、成盐等反应合成了6个新的目标化合物( 7a-7f )，结构已通过ESI-MS、1H NMR、IR及HR-MS确证。初步药理活性实验结果表明，受试化合物具有中等强度的α1-肾上腺素受体拮抗活性，其中目标化合物 7e pA2值大于7.00，有进一步研究的价值。运用Sybyl软件对本类化合物开展了3D-QSAR研究，结合本课题组前期工作，构建了1-(1,4-苯并二噁烷-2-羰基)-4-取代芳氧烷基哌嗪类化合物的CoMFA模型，q2=0.753，r2=0.986，为该类α1受体拮抗剂进一步的结构优化提供了理论依据。Abstract: In order to search for new α1-adrenoceptor antagonists bearing 1,4-benzodioxane moiety,six new target compounds ( 7a-7f ) were synthesized from catechol via ring-closing,hydrolysis,amidation，substitution and salt formation. Their structures were confirmed by ESI-MS, 1H NMR，IR and HR-MS. Preliminary biological evaluation result showed that most of the target compounds had modest blocking activity against α1-adrenoceptor and the pA2 value of 7e was greater than 7.00. 3D-QSAR study of the title compounds was performed via Sybyl software. Based on our previous work，CoMFA model was constructed from eighteen 1-(1,4-benzodioxan-2-ylcaronyl)- 4-aryloxy-alkyl-piperazine analogues (q2=0.753,r2=0.986)，and these results would be helpful for further structural optimization of 1,4-benzodioxane α1-adrenoceptor antagonists.
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Keywords:
- benign prostatic hyperplasia /
- α1-adrenoceptor antagonists /
- 1,4-benzodioxane /
- synthesis /
- CoMFA /
- 3D-QSAR
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