芳基四氮唑烷基侧链新型酮内酯的合成与抗菌活性研究
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摘要
大环内酯类抗生素是由链霉菌产生的一类弱碱性抗生素及其结构修饰产物,在临床上主要用于治疗呼吸道感染、消化道感染、皮肤及软组织感染。随着抗生素长期广泛使用以及滥用,许多病原菌对大环内酯类抗生素产生耐药性,严重影响其在临床上的疗效,甚至导致治疗失败。因此,开发新的抗耐药菌大环内酯类抗生素是当前药物研究的热点之一。
酮内酯是近年来研究开发的第三代大环内酯类抗生素,这种结构不仅对酸稳定而且无诱导耐药性。酮内酯类化合物的作用靶点是23SrRNA的V区A2058和II区的A752,发挥了对敏感菌和耐药菌强大的抗菌活性。研究表明脱去C3位克拉定糖可以克服大环内酯的诱导耐药性；通过C11,12位的氨基甲酸内酯环上侧链修饰也可以进一步改善其药代动力学性质。
本文主要研究芳基四氮唑烷基为侧链酮内酯化合物的合成及其抗菌活性研究。首先综述了近年来酮内酯抗生素的研究进展。利用已有文献资料的酮内酯结构及其抗菌活性,采用比较分子力场分析(CoMFA)和比较分子相似性分析(CoMSIA)方法,建立有酮内酯类化合物的3D-QSAR模型。CoMFA模型中,其交叉验证系数rcv2为0.699,非正交验证系数r2为0.945,,相对应立体场和静电场贡献比分别为0.638和0.362；CoMSIA模型中,其交叉验证系数rcv2为0.630,非正交验证系数r2为0.925,相对应立体场、静电场、疏水场、氢键供体场和氢键受体场的贡献比分别为0.208、0.244、0.279、0.045和0.223。用两种模型分别预测检验集分子的活性,结果与实验值较吻合,说明所建立的模型具有较好的预测能力。通过分析CoMFA和CoMSIA等势图,可为优化酮内酯类化合物的结构提供理论指导。本文通过对已有酮内酯氨基甲酸内酯环侧链化合物的分析,设计了以芳基四氮唑烷基为侧链替代泰利霉素的侧链合成新型酮内酯化合物。
以芳基腈或芳基醛与叠氮化钠反应得到芳基四氮唑化合物,再与N-溴烷基邻苯二甲酰亚胺进行取代反应,然后肼解得到17个芳基四氮唑烷基胺化合物。
参照泰利霉素的合成方法,以克拉霉素为起始原料,分别通过两条路线各5步反应得到中间体化合物3-脱克拉定糖-3-氧代-6-O-甲基-10,11-脱氢-2'-苯甲酰基红霉素(10),再与N,N-羰基二咪唑反应得到中间体3-脱克拉定糖-3-氧代-6-O-甲基-10,11-脱氢-12-O-咪唑羰酰基-2'-苯甲酰基红霉素(11),然后与上述芳基四氮唑烷基胺反应,最后脱去苯甲酰基保护基,得到17个芳基四氮唑烷基为侧链新型酮内酯化合物。
本文共合成得到了51个未见文献报道的新化合物,其中17个为芳基四氮唑烷基异吲哚-1,3-2H-二酮化合物,17个为芳基四氮唑烷基胺化合物,17个为芳基四氮唑烷基为侧链新型酮内酯化合物。所得到的新的目标化合物均经过MS、1H NMR、13C NMR和HRMS结构确证。
采用微量肉汤二倍稀释法,以金黄色葡萄球菌、绿脓杆菌和大肠杆菌为试验菌,红霉素和克拉霉素为对照药,测定了目标化合物的体外最低抑菌浓度,对新的酮内酯化合物的抗菌活性进行了评价。体外抗菌活性实验结果证实,目标化合物对敏感金葡菌均具有良好的抗菌活性,多数化合物优于红霉素和克拉霉素；所有化合物对耐药金葡菌有良好的抗菌活性；而对绿脓杆菌和大肠杆菌也显示了较好的抗菌活性,与红霉素和克拉霉素相比,有不同程度的改善。其中,化合物12e显示了对所有试验菌株都有良好的抗菌活性,说明侧链杂环为(吡啶-2-基)四氮唑基的抗菌活性有所增加,具有进一步研究的潜力。
Macrolides are a class of weak base antibiotics produced by Streptomycetes, and their derivatives. They have been widely used for the clinical treatment of the infection of respiratory system, digestive system, skin and soft tissue. Due to the extensive and abuse use of the antibiotics, the problem of bacterial resistance to macrolides has led to a decrease in therapeutic effect, and even no effect. Therefore, it has been an attracted attention to develop new potent macrolides against resistant pathogens.
Recently the ketolides have been developed as the third generation of macrolides. The structure of ketolide is stable to acid and with no induction drug resistance. The action target of ketolides is A2058 in domain V and A752 in domainⅡof 23S rRNA. Removal of C3 cladinosyl can overcome the induction drug resistance to macrolides, and the side chain modification of C11,12 position can improve the pharmacokinetics property.
In this thesis, novel ketolides bearing aryl-tetrazolyl alkyl-substituted chains were designed and synthesized, their antibacterial activities were explored against different bacteria. First the recent progress of the ketolides research was reviewed. Then 3D-QSAR studies are performed on a series of ketolides and their antibacterial activity by using CoMFA and CoMSIA methods. For CoMFA model, a good cross-validated correlation coefficient (r2cv) of 0.699 and a high non-cross-validated correlation coefficient (r2) of 0.945 was obtained, the contributions of steric and electrostatic fields were 0.638 and 0.362. For CoMSIA model, a good cross-validated correlation coefficient (r2cv) of 0.630 and a high non-cross-validated correlation coefficient (r2) of 0.925 was obtained, the contributions of steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields of this model were 0.208,0.244,0.279,0.045 and 0.223, respectively. These results indicated that two models were significant and had good predictability. The resulting 3D contour maps of CoMFA and CoMSIA models provide useful guidance for designing ketolide derivatives for better antibacterial activity. From the results analysis of side chains, aryl-tetrazolyl alkyl-substituted chains were designed to replace the side chain of Telithromycin to synthesize new ketolides.
Tetrazoles were synthesized starting from the aryl-nitriles or aryl-aldehydes. The N-alkyklation on the resulting aryl-tetrazol was carried out with N-bromoalkyl-phthalimide to produce N-aryl-tetrazolalkyl-phthalimides, which are hydrazinolysized to yield aryl-tetrazolyl contained alkyl-amines.
Starting from clarithromycin, compound 10 was synthesized through two methods, in five steps respectively. Deprotonation of the C12 hydroxyl of compound 10 with sodium hydride in the presence of carbonyldiimidazole gave the corresponding C12 imidazoly carbamate 11. The resulting compound 11 was upon reaction with an excess of side chain amine, and deprotection of the desosamine benzoate yielded the novel aryl-tetrazolyl contained alkyl-substituted C11, 12-cyclic carbamate ketolides.
Fifty-one novel compounds, including seventeen novel N-aryl-tetrazolalkyl-phthalimides, seventeen novel aryl-tetrazolyl alkyl-amines and seventeen novel aryl-tetrazolyl alkyl-substituted ketolides, were obtained in this thesis. All the structures of new ketolides were identified by MS, 1H NMR, 13C NMR and HRMS.
All of the target ketolides were tested for in virto antibacterial activities against three strains are S. aureus, P. aeruginosa and E. coli by using erythromycin and clarithromycin as referenc compounds. The activities were reported as minimum inhibitory concentrations, which were determined by the broth microdilution method. The results showed that all the compounds synthesized were potent against erythromycin-susceptible and erythromycin-resistant S. aureus, and many compounds demonstrated more active against erythromycin-susceptible S. aureus comparable to erythromycin and clarithromycin. All the compounds proved more or less impoved activity against P. aeruginosa and E. coli. Compound 12e exhibited improved activity agaist all the erythromycin-susceptible and erythromycin-resistant strains, which indicated that when the heter cyclic ring of the terminal in the side chain was 5-(pyridin-2-yl)-1H-tetrazol-1-yl can enhance antibacterial activity. This study presented a considerable opportunity for the development of new anticbiotics.
酮内酯是近年来研究开发的第三代大环内酯类抗生素,这种结构不仅对酸稳定而且无诱导耐药性。酮内酯类化合物的作用靶点是23SrRNA的V区A2058和II区的A752,发挥了对敏感菌和耐药菌强大的抗菌活性。研究表明脱去C3位克拉定糖可以克服大环内酯的诱导耐药性；通过C11,12位的氨基甲酸内酯环上侧链修饰也可以进一步改善其药代动力学性质。
本文主要研究芳基四氮唑烷基为侧链酮内酯化合物的合成及其抗菌活性研究。首先综述了近年来酮内酯抗生素的研究进展。利用已有文献资料的酮内酯结构及其抗菌活性,采用比较分子力场分析(CoMFA)和比较分子相似性分析(CoMSIA)方法,建立有酮内酯类化合物的3D-QSAR模型。CoMFA模型中,其交叉验证系数rcv2为0.699,非正交验证系数r2为0.945,,相对应立体场和静电场贡献比分别为0.638和0.362；CoMSIA模型中,其交叉验证系数rcv2为0.630,非正交验证系数r2为0.925,相对应立体场、静电场、疏水场、氢键供体场和氢键受体场的贡献比分别为0.208、0.244、0.279、0.045和0.223。用两种模型分别预测检验集分子的活性,结果与实验值较吻合,说明所建立的模型具有较好的预测能力。通过分析CoMFA和CoMSIA等势图,可为优化酮内酯类化合物的结构提供理论指导。本文通过对已有酮内酯氨基甲酸内酯环侧链化合物的分析,设计了以芳基四氮唑烷基为侧链替代泰利霉素的侧链合成新型酮内酯化合物。
以芳基腈或芳基醛与叠氮化钠反应得到芳基四氮唑化合物,再与N-溴烷基邻苯二甲酰亚胺进行取代反应,然后肼解得到17个芳基四氮唑烷基胺化合物。
参照泰利霉素的合成方法,以克拉霉素为起始原料,分别通过两条路线各5步反应得到中间体化合物3-脱克拉定糖-3-氧代-6-O-甲基-10,11-脱氢-2'-苯甲酰基红霉素(10),再与N,N-羰基二咪唑反应得到中间体3-脱克拉定糖-3-氧代-6-O-甲基-10,11-脱氢-12-O-咪唑羰酰基-2'-苯甲酰基红霉素(11),然后与上述芳基四氮唑烷基胺反应,最后脱去苯甲酰基保护基,得到17个芳基四氮唑烷基为侧链新型酮内酯化合物。
本文共合成得到了51个未见文献报道的新化合物,其中17个为芳基四氮唑烷基异吲哚-1,3-2H-二酮化合物,17个为芳基四氮唑烷基胺化合物,17个为芳基四氮唑烷基为侧链新型酮内酯化合物。所得到的新的目标化合物均经过MS、1H NMR、13C NMR和HRMS结构确证。
采用微量肉汤二倍稀释法,以金黄色葡萄球菌、绿脓杆菌和大肠杆菌为试验菌,红霉素和克拉霉素为对照药,测定了目标化合物的体外最低抑菌浓度,对新的酮内酯化合物的抗菌活性进行了评价。体外抗菌活性实验结果证实,目标化合物对敏感金葡菌均具有良好的抗菌活性,多数化合物优于红霉素和克拉霉素；所有化合物对耐药金葡菌有良好的抗菌活性；而对绿脓杆菌和大肠杆菌也显示了较好的抗菌活性,与红霉素和克拉霉素相比,有不同程度的改善。其中,化合物12e显示了对所有试验菌株都有良好的抗菌活性,说明侧链杂环为(吡啶-2-基)四氮唑基的抗菌活性有所增加,具有进一步研究的潜力。
Macrolides are a class of weak base antibiotics produced by Streptomycetes, and their derivatives. They have been widely used for the clinical treatment of the infection of respiratory system, digestive system, skin and soft tissue. Due to the extensive and abuse use of the antibiotics, the problem of bacterial resistance to macrolides has led to a decrease in therapeutic effect, and even no effect. Therefore, it has been an attracted attention to develop new potent macrolides against resistant pathogens.
Recently the ketolides have been developed as the third generation of macrolides. The structure of ketolide is stable to acid and with no induction drug resistance. The action target of ketolides is A2058 in domain V and A752 in domainⅡof 23S rRNA. Removal of C3 cladinosyl can overcome the induction drug resistance to macrolides, and the side chain modification of C11,12 position can improve the pharmacokinetics property.
In this thesis, novel ketolides bearing aryl-tetrazolyl alkyl-substituted chains were designed and synthesized, their antibacterial activities were explored against different bacteria. First the recent progress of the ketolides research was reviewed. Then 3D-QSAR studies are performed on a series of ketolides and their antibacterial activity by using CoMFA and CoMSIA methods. For CoMFA model, a good cross-validated correlation coefficient (r2cv) of 0.699 and a high non-cross-validated correlation coefficient (r2) of 0.945 was obtained, the contributions of steric and electrostatic fields were 0.638 and 0.362. For CoMSIA model, a good cross-validated correlation coefficient (r2cv) of 0.630 and a high non-cross-validated correlation coefficient (r2) of 0.925 was obtained, the contributions of steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields of this model were 0.208,0.244,0.279,0.045 and 0.223, respectively. These results indicated that two models were significant and had good predictability. The resulting 3D contour maps of CoMFA and CoMSIA models provide useful guidance for designing ketolide derivatives for better antibacterial activity. From the results analysis of side chains, aryl-tetrazolyl alkyl-substituted chains were designed to replace the side chain of Telithromycin to synthesize new ketolides.
Tetrazoles were synthesized starting from the aryl-nitriles or aryl-aldehydes. The N-alkyklation on the resulting aryl-tetrazol was carried out with N-bromoalkyl-phthalimide to produce N-aryl-tetrazolalkyl-phthalimides, which are hydrazinolysized to yield aryl-tetrazolyl contained alkyl-amines.
Starting from clarithromycin, compound 10 was synthesized through two methods, in five steps respectively. Deprotonation of the C12 hydroxyl of compound 10 with sodium hydride in the presence of carbonyldiimidazole gave the corresponding C12 imidazoly carbamate 11. The resulting compound 11 was upon reaction with an excess of side chain amine, and deprotection of the desosamine benzoate yielded the novel aryl-tetrazolyl contained alkyl-substituted C11, 12-cyclic carbamate ketolides.
Fifty-one novel compounds, including seventeen novel N-aryl-tetrazolalkyl-phthalimides, seventeen novel aryl-tetrazolyl alkyl-amines and seventeen novel aryl-tetrazolyl alkyl-substituted ketolides, were obtained in this thesis. All the structures of new ketolides were identified by MS, 1H NMR, 13C NMR and HRMS.
All of the target ketolides were tested for in virto antibacterial activities against three strains are S. aureus, P. aeruginosa and E. coli by using erythromycin and clarithromycin as referenc compounds. The activities were reported as minimum inhibitory concentrations, which were determined by the broth microdilution method. The results showed that all the compounds synthesized were potent against erythromycin-susceptible and erythromycin-resistant S. aureus, and many compounds demonstrated more active against erythromycin-susceptible S. aureus comparable to erythromycin and clarithromycin. All the compounds proved more or less impoved activity against P. aeruginosa and E. coli. Compound 12e exhibited improved activity agaist all the erythromycin-susceptible and erythromycin-resistant strains, which indicated that when the heter cyclic ring of the terminal in the side chain was 5-(pyridin-2-yl)-1H-tetrazol-1-yl can enhance antibacterial activity. This study presented a considerable opportunity for the development of new anticbiotics.
引文
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