诺蒎酮-噻唑腙类化合物的合成及抑菌活性

synthesis and antibacterial activity of nopinone-based thiazolyhydrazone compounds

摘要:

以β-蒎烯为原料经选择性氧化制得的诺蒎酮，再经羟醛缩合、酰腙化和环化反应得到15个的诺蒎酮-噻唑腙类化合物；采用1H NMR、13C NMR 和 HR-MS对所合成化合物的结构进行了表征；探索了所合成化合物对金黄色葡萄球菌、白色念珠菌和肺炎克雷伯氏菌的抑菌活性。结果表明，化合物2-{2-{6,6-二甲基-3-(4-硝基苯亚甲基)二环[3.1.1]庚-2-亚基}肼基}-4-(4-氟苯基)噻唑（Ⅲe）、4-{2-{2-{6,6-二甲基-3-(4-硝基苯亚甲基)二环[3.1.1]庚-2-亚基}肼基}噻唑-4-基}苯酚（Ⅲf）、2-{2-{3-(4-氟亚苄基)-6,6-二甲基双环[3.1.1]庚-2-亚基}肼基}-4-苯基噻唑（Ⅲg）和2-{2-{6,6-二甲基-3-(4-甲基亚苄基)二环[3.1.1]庚-2-亚基}肼基}-4-苯基噻唑（Ⅲj）对金黄色葡萄球菌抑菌效果显著，其最低抑菌质量浓度分别为3.51 μg/L、0.88 μg/L、7.03 μg/L和3.52 μg/L；化合物4-{2-{2-(3-亚苄基-6,6-二甲基二环[3.1.1]庚烷-2-亚基)肼基}噻唑-4-基}苯酚（Ⅲc）对白色念珠菌有较好的抑菌活性，最低抑菌质量浓度为28.12 μg/L；所有目标化合物对肺炎克雷伯氏菌的抑菌效果并不显著。从构效关系看：R1和R2上取代基的不同对化合物抑制金黄色葡萄球菌效果有明显的影响，当R1为强吸电子基团时能显著提高化合物的抑菌活性，其中化合物Ⅲf对金黄色葡萄球菌的抑制效果与硫酸卡纳霉素的抑制效果相当，具有潜在的开发价值。 关键词：-蒎烯；诺蒎酮；噻唑腙；抑菌活性

Abstract:

A series of nopinone thiazolidazone drivatives were obtained from nopinone by aldol condensation, acylhydration and cyclization, therein nopinone was obtained from -piene by xidation reactions. All the target compounds were structurally characterized by 1H NMR, 13C NMR and HR-MS, and the antibacterial activitesof these compounds against Staphylococcus aureus, Candida albicans and Klebsiella pneumoniawereinvestigated. The results showed that 2-{2-{6,6-dimethyl-3-(4-nitrobenzylidene)bicyclo[3.1.1]heptan-2-ylidene}hydrazinyl}-4-(4-fluorophenyl)thiazole (Ⅲe), 4-{2-{2-{6,6-dimethyl-3-(-4-nitrobenzylidene)bicyclo[3.1.1]heptan-2-ylidene}hydrazinyl}thiazol-4-yl}phenol (Ⅲf), 2-{2-{3-(4-fluorobenzylidene)-6,6-dimethylbicyclo[3.1.1]heptan-2-ylidene}hydrazinyl}-4-phenylthiazole (Ⅲg), 2-{2-{6,6-dimethyl-3-(4-methylbenzylidene)bicyclo[3.1.1]heptan-2-ylidene}hydrazinyl}-4-phenylthiazole (Ⅲj) had significant inhibitory effect on staphylococcus aureus, and the minimum inhibitory mass concentration was 3.51 μg/L, 0.88 μg/L, 7.03 μg/L and 3.52 μg/L, respectively; 4-{2-{2-(3-benzylidene-6,6-dimethylbicyclo[3.1.1]heptan-2-ylidene)hydrazinyl}thiazol-4-yl}phenol (Ⅲc) had good inhibitory activity on Candida albicans, and the minimum inhibitory mass concentration was 28.12 μg/L. However, all the target compounds had no significant inhibitory effect on Klebsiella pneumoniae. It was indicated that the difference of the substituent groups R1 and R2 leaded different inhibiting activities of the target compound to Staphylococcus aureus from the structure-activity relationship. When R1 is a strong electron-withdrawing group, the antibacterial activity of the compound significantly improved, especially, the inhibitory effect of compound Ⅲf to Staphylococcus aureus is comparable to that of kanamycin sulfate, which has potential development value.