Antibacterial activity and structure-activity relationships of berberine analogs
Antibacterial activity and structure-activity relationships of berberine analogs
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DOI：
10.1016/0223-5234(96)85167-1
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发表时间：
1996-01-01
影响因子：
6.7
通讯作者：
Taniguchi, M
中科院分区：
文献类型：
--
作者：
Iwasa, K;Kamigauchi, M;Taniguchi, M
制备小檗碱1和相关化合物的类似物以评价结构-活性关系。在13-烷基取代的和13-未取代的原小檗碱盐中，13-乙基-9-乙氧基同系物30、13-乙基类似物29和13-甲基衍生物3显示出对金黄色葡萄球菌的抗菌活性分别比母体碱小檗碱1增加8倍、4倍和2倍;这表明空间效应在抗菌中起重要作用。活动还原原berinium盐产生的四氢衍生物大大降低了抗菌活性。甲二氧基取代环A的C-2和C-3处的甲氧基导致抗菌活性增加。这些数据有力地表明，增强的活性需要季氮原子（如原小檗鎓盐中的季氮原子）、C-13处的烷基取代基和C-2和C-3处的亚甲二氧基官能团。四氢原小檗碱α-N-甲氧基盐显示出比四氢原小檗碱盐酸盐更高的活性，但比原小檗碱盐明显更低的活性。在α-N-甲氧基盐中C-13和环A上的取代的影响与原小檗碱盐中的那些类似。立体化学变化的B/C环交界处从反式顺式，并在C-13的甲基从α到β，分别有显着和轻微的影响的活动。测试化合物对大肠杆菌（革兰氏阴性细菌）和白色念珠菌（真菌）的活性低于金黄色葡萄球菌（革兰氏阳性细菌）。
Analogs of berberine 1 and related compounds were prepared to evaluate structure-activity relationships. Among the 13-alkyl-substituted and the 13-unsubstituted protoberberinium salts, the 13-ethyl-9-ethoxyl homolog 30, the 13-ethyl analog 29, and the 13-methyl derivative 3 showed an increase in antibacterial activity against Staphylococcus aureus by eight-, four- and twofold respectively over the parent base berberine 1; this is suggestive that steric effects play a significant role in the antibacterial. activity. Reduction of the protoberberinium salts yielding the tetrahydro derivatives greatly reduced the antibacterial activity. Replacement of methoxyl groups at the C-2 and the C-3 of ring A by a methylenedioxy group resulted in increased antibacterial activity. These data strongly suggest that the quaternary nitrogen atom such as in protoberberinium salts, an alkylsubstituent at C-13, and a methylenedioxy function at C-2 and C-3 are required for enhanced activity. Tetrahydroprotoberberine alpha-N-metho salts showed higher activity than tetrahydroprotoberberine hydrochlorides, but appreciably lower activity than protoberberinium salts. The effects of substitution at C-13 and on ring A in the alpha-N-metho salt were similar to those in protoberberinium salts. Stereochemical changes of the B/C ring juncture from trans to cis, and of the methyl group at C-13 from alpha to beta, had, respectively, marked and slight effects on the activity. The tested compounds were less active against Escherichia coli (Gram-negative bacterium) and Candida albicans (fungus) than S aureus (Gram-positive bacterium).