3-取代硫基-5-(2-羟基苯基)-4H-1,2,4-三唑类化合物抑菌活性的定量构效关系和结构修饰的理论研究

Theoretical Studies on Quantitative Structure-Activity Relationship and Structural Modification for 3-Substituted Sulfur-5-(2-Hydroxyphenyl)-4H-1,2,4-Triazole Compounds

用DFT-B3LYP方法,在基组6-31G水平,对24种3-取代硫基-5-(2-羟基苯基)-4H-1,2,4-三唑类化合物分子进行几何优化,并计算了EHOMO,ELUMO,ENHOMO,ENLUMO,QC1～QC8,QN1～QN3,QO,QS和ΔE1,ΔE2,ΣQ等量子化学描述符(qc).通过最佳变量子集回归建立13种上述化合物对大肠杆菌、白色念珠菌、金黄色葡萄球菌等抑菌活性(AJ:Ae,Am和As)的QSAR模型.对于大肠杆菌的Ae模型的相关系数(R2)和逐一剔除法交叉验证系数Rcv2依次为0.930和0.871,相应白色念珠菌Am模型为0.926和0.869,As模型为0.781和0.572.通过Radj2,F,Rcv2,VIF,AIC,FIT等检验,上述模型具有令人满意的稳健性和预测能力.结果显示ΔE1和ΣQ直接影响这些化合物的生物活性:ΣQ增大,其抑菌活性增强;ΔE1越高,AJ下降.据此提出三唑类化合物分子可能的抑菌机理.由此发现,在三唑类化合物分子的R中合适部位选用吸电子能力较强的取代基团进行结构修饰,有利于提高被修饰后分子的抑菌活性.根据对R进行结构修饰(共提出11种化合物),得出4种抑菌活性均超出100%的三唑类化合物(质量分数为0.01%),希望将来得到生物实验的证实.

The DFT-B3LYP method,with the basis set 6-31G,was employed to calculate the molecular geometries and electronic structures of 24 3-substituted sulfur-5-（2-hydroxyphenyl）-4H-1,2,4-triazole com-pounds.EHOMO,ELUMO,ENHOMO,ENLUMO,QC1～QC8,QN1～QN3,QO,QS,ΔE1,ΔE2,ΣQ were selected as quantum chemical descriptors（qc）.The quantitative structure-activity relationships（QSAR） were established by using leaps-and-bounds regression analysis for the antibacterial activities（AJ： Am,Ae and As） of 13 com-pounds to Escherichia coli,Monilia albican and Staphylococcus aureus along with the qc.The correlation coefficients（R2） and the leave-one-out（LOO） cross validation Rcv2 for the Ae,Am and As models were 0.930 and 0.871;0.926 and 0.869;0.781 and 0.572 respectively.The QSAR models have both favorable estimation stability and good prediction capability by Radj2,F,Rcv2,VIF,AIC,FIT tests.The results indicate that the ΔE1 and ΣQ are main factors which can affect the bioactivities of these compounds directly.The antibacte-rial activities of the compounds increase with the increase of the ΣQ;however the higher the ΔE1 is,the lower the AJ is.The possible mechanism has been given for the antibacterial of the triazole compounds.It is known that the suitable structural modifications of R group in triazole compounds with the strong elec-tron-attracting one are beneficial to the antibacterial activities.According to the results（11 compounds） ob-tained from the structural modifications,the antibacterial activities of four modified molecules are over 100% when mass fraction is 0.01%,and it is expected to be confirmed by using biologic experiments.