2,4-二氨基喹唑啉衍生物的抑菌活性研究

Antibacterial activity of piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline

喹唑啉衍生物具有广泛的生物活性,包括抗菌活性。为发现此类化合物中具有潜在抑菌活性的化合物,本研究考察了15种带有哌嗪二硫代甲酸酯侧链的2,4-二氨基喹唑啉衍生物7a^7o的抑菌活性。首先采用分子对接方法对底物与酶的结合能进行预测,并用标准2倍稀释法测定这15种化合物对多重耐药大肠埃希菌的最小抑菌浓度(minimum inhibitory concentration,MIC)。结果表明,15种化合物与阳性对照相比均具有较好的抑菌活性。化合物7a、7g和7k具有明显的抑菌活性,其MIC均≤1mg/mL。进一步采用高效毛细管电泳筛选模型对7a、7g和7k进行分子水平抑菌实验,分别测定其抑制率与半数抑制浓度(half inhibitory concentration,IC50),发现化合物7k具有最佳抑制活性(IC_(50)为4.97×10^(-2) mg/mL)。此外,对15种化合物抑菌活性构效关系的研究表明,苯环上连有吸电子基团的哌嗪二硫代甲酸酯侧链对抑菌活性有贡献。这一研究有望为抑菌药物的研发提供有效的先导化合物。

Antibacterial activity of fifteen piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline was investigated in order to search for compounds with efficient antibacterial activity.First,the binding energies of substrate-enzyme were predicted by molecular docking calculation.Second,minimum inhibitory concentration（MIC）values of the tested compounds were measured against the multidrug-resistant Escherichia coli（E.coli）with a standard method.The results showed that some compounds had better antibacterial activity than the control,and MIC of compounds 7a,7g and 7k was below 1 mg/mL.The results were further confirmed by high performance capillary electrophoresis（HPCE）screening method,and the half inhibitory concentration（IC_（50））of 7kwas 4.97×10^（-2） mg/mL.In addition,structure-activity relationship analysis showed that the presence of an electron-withdrawing group at the C2-position of phenyl ring linked with piperazine moiety was favorable to the antibacterial activity.This study provided a new option for the development of antimicrobial agents.