吡嗪类碳酰肼化合物与CT-DNA相互作用及体外抑菌活性  

Interactions between Pyrazine Carbazide Compounds with CT-DNA and In Vitro Antibacterial Activity

作　　者：张余珍 刘向荣[1,2] 杨再文 赵顺省[1,2] ZHANG Yuzhen;LIU Xiangrong;YANG Zaiwen;ZHAO Shunsheng(College of Chemistry and Chemical Engineering,Xi′an University of Science and Technology,Xi′an 710054,China;Key Laboratory of Coal Resources Exploration and Comprehensive Utilization of MNR,Xi′an 710021,China)

机构地区：[1]西安科技大学化学与化工学院,陕西西安710054 [2]自然资源部煤炭资源勘查与综合利用重点实验室,陕西西安710021

出　　处：《合成化学》2023年第1期40-51,共12页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(U1903133)。

摘　　要：以5-氯吡嗪-2-羧酸甲酯和水合肼为原料,经亲核取代和脱水缩合反应合成了3种新型吡嗪类碳酰肼化合物C_(13)H_(14)N_(6)O(a)、C_(13)H_(14)N_(6)O_(2)(b)和C_(12)H_(12)N_(6)O_(2)(c)。采用元素分析与核磁共振氢谱对化合物a~c进行了表征,结果表明合成的产物即为目标化合物。通过溶剂挥发法培养得到了化合物a的单晶并利用X-射线单晶衍射测定化合物a的晶体结构为单斜晶系。根据紫外-可见光谱可知,化合物a~c均以插入模式与CT-DNA作用。利用微量热实验测定了化合物a~c与CT-DNA的相互作用,发现反应过程放热,热效应ΔH依次为-5.77×10^(3)、-5.50×10^(3)和-5.96×10^(3)kJ·moL^(-1),反应时间均小于40 min。通过分子对接模拟计算明确了化合物a和化合物b与DNA的具体结合位点包括A链DC4和DG5以及B链DC4、DG5和DA6,化合物c与DNA的具体结合位点包括A链DC4和DG5以及B链DC4和DG5。采用牛津杯法测定了化合物a~c对枯草芽孢杆菌、金黄色葡萄球菌、铜绿假单胞菌以及大肠杆菌四种细菌的抑菌活性,结果表明化合物a~c均对铜绿假单胞菌表现出优于阳性对照组四环素的抑菌活性。Three novel pyrazine carbazide compounds C_(13)H_(14)N_(6)O(a),C_(13)H_(14)N_(6)O_(2)(b)and C_(12)H_(12)N_(6)O_(2)(c)were synthesized from methyl 5-chloropyrazine-2-carboxylate and hydrazine hydrate by nucleophilic substitution and dehydration condensation reaction.Compounds a~c were characterized by elemental analysis and 1 H NMR,which indicated the synthesized products were the target compounds.The single crystal of compound a was obtained by solvent evaporation method,and its crystal structure was determined to be monoclinic by X-ray single crystal diffraction.According to the UV-vis spectroscopy,compounds a~c interacted with CT-DNA in an insertion mode.Interactions between compounds a~c and CT-DNA were measured by microcalorimetric experiment.It was found that the reaction processes were exothermic,the thermal effectsΔH were-5.77×10^(3),-5.50×10^(3)and-5.96×10^(3)kJ·moL^(-1)respectively,and the reaction time were less than 40 min.The results of the molecular docking simulation calculation showed that the specific binding sites of compounds a and b interacting with DNA included A-chain DC4 and DG5 as well as B-chain DC4,DG5 and DA6,the binding sites of compound c interacting with DNA included A-chain DC4 and DG5 as well as B-chain DC4 and DG5.The antibacterial activities of compounds a~c against B.subtilis,S.aureus,P.aeruginosa and E.coli were determined by Oxford cup method,and the results displayed that compounds a~c all exhibited better antibacterial activities against P.aeruginosa than the positive control tetracycline.

关 键 词：碳酰肼 CT-DNA相互作用 微量热 分子对接 抑菌 

分 类 号：O626.3[理学—有机化学]