以对氨基水杨酸为母核的三分子缀合物的合成及其生物活性研究  

Synthesis and biological activities of three-molecule conjugates with para-aminosalicylic acid as parent nucleus

作　　者：任艳会 范莉 许峻旗 谢建平[2] 代乐平 毛丹 杨茜 杨大成 REN Yan-hui;FAN Li;XU Jun-qi;XIE Jian-ping;DAI Le-ping;MAO Dan;YANG Xi;YANG Da-cheng(Key Laboratory of Applied Chemistry of Chongqing Municipality,School of Chemistry and Chemical Engineering,Southwest University,Chongqing 400715,China;College of Life Science,Southwest University,Chongqing 400715,China)

机构地区：[1]西南大学化学化工学院,重庆市高校应用化学重点实验室,重庆400715 [2]西南大学生命科学学院,重庆400715

出　　处：《药学学报》2022年第7期2126-2138,共13页Acta Pharmaceutica Sinica

基　　金：重庆市技术创新与应用发展专项面上项目(cstc2019jscx-msxmX0123);重庆市大学生创新创业训练计划项目(S202110635052)。

摘　　要：基于多靶点药物设计思想,以对氨基水杨酸(PAS)为母核,选用不同的连接子将PAS、异烟酸和氟喹诺酮三种结构单元缀合,设计了未见文献报道的目标分子TM1和TM2;经多步反应合成了16个目标分子,测试了目标分子抗结核及抗人致病菌的活性。测试结果表明,TM2a抗结核活性强于所测试的氟喹诺酮,TM1a与阳性对照药物氟喹诺酮中活性最强的克林沙星相当;TM1a对所测试菌株都显示最强抑制活性,TM1b与TM2a对多数菌株显示很强抑制活性,TM1h/2h对部分菌株具有强抑制活性;TM1a/1h对金葡菌ATCC14125的抑制活性远强于所测试的氟喹诺酮,值得进一步研究。溶血性实验结果表明,高活性分子TM1a和TM2a分别在8及32μg·mL^(-1)浓度下表现出相对安全性。本研究首次合成了PAS为母核的三分子药效团拼接的新型分子,部分分子具有非常强的抑菌活性,为抗菌药物的研发提供了新的思路。Based on the idea of multi-target drug design,taking p-aminosalicylic acid(PAS)as the parent nucleus,the unreported target molecules TM1 and TM2 were designed with PAS,isonicotinic acid and fluoroquinolone as three structural units conjugated by different linkers.Sixteen target molecules were synthesized by multi-step reaction,and their activities against Mycobacterium tuberculosis and human pathogenic bacteria were evaluated.The results showed that the anti-tuberculosis activity of TM2a was stronger than those of the assayed fluoroquinolones,while TM1a was comparable to that of clinafloxacin,the most active compound of the positive control fluoroquinolones;TM1a showed the strongest inhibitory activity to all almost tested strains,TM1b and TM2a showed very strong inhibitory activity to most strains,and TM1h/2h had strong inhibitory activity to some strains;The inhibitory activities of TM1a/1h on Staphylococcus aureus ATCC14125 are much stronger than those of fluoroquinolones,which eminently deserves further study.The hemolysis test results showed that the highly active molecules TM1a and TM2a exhibited relative safety below the concentrations of 8 and 32μg·mL^(-1),respectively.In this study,a new hybrid molecule of three molecular pharmacophores with PAS as the parent nucleus was synthesized for the first time,and some of which have highly strong antibacterial activity,which provides a new idea for the research and development of antibiotics.

关 键 词：对氨基水杨酸 异烟酸 氟喹诺酮 抗结核活性 抗人致病菌活性 

分 类 号：R914[医药卫生—药物化学]