NEW BENZYLPYRIMIDINES - INHIBITION OF DHFR FROM VARIOUS SPECIES, QSAR, COMFA AND PC ANALYSIS
NEW BENZYLPYRIMIDINES - INHIBITION OF DHFR FROM VARIOUS SPECIES, QSAR, COMFA AND PC ANALYSIS
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DOI：
10.1016/0223-5234(96)88297-3
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发表时间：
1995-01-01
影响因子：
6.7
通讯作者：
SEYDEL, JK
中科院分区：
文献类型：
--
作者：
CZAPLINSKI, KH;HANSEL, W;SEYDEL, JK
为了进一步分析负责新开发的高活性苄基嘧啶K-130的增强活性的结构要求，合成了一系列具有各种4-苯胺基烷氧基部分的甲氧苄啶类似物，并对来自各种物种（Lufu分枝杆菌、大肠杆菌、白色念珠菌和大鼠）的二氢叶酸还原酶（DHFR）进行了测试。仲氨基对于结合亲和力的重要性可以通过改变仲氨基部分的对位的取代基来显示。多元线性回归和比较分子力场分析（CoMFA）支持这一发现。极化的SO2基团被认为是K-130活性增加的原因，但似乎不是唯一对受体结合重要的基团。此外，通过PC分析显示，与来自大鼠肝脏的DHFR相比，新化合物对来自各种细菌和白色念珠菌的DHFR具有高选择性。
To further analyze the structural requirements responsible for the enhanced activity of the newly developed, highly active benzylpyrimidine K-130, a series of trimethoprim analogues with various 4-anilinoalkoxy moieties has been synthesized and tested against dihydrofolate reductase (DHFR) derived from various species (Mycobacterium lufu, Escherichia coli, Candida albicans and rats). The importance of the secondary amino group for binding affinity could be shown by varying the substituent in the para position to the sec-amino moiety. This finding could be supported by multiple linear regression and comparative molecular field analysis (CoMFA). The polarized SO2, group, which was thought to be responsible for the increased activity of K-130, seems not to be the only group Important for receptor binding. Additionally, a high selectivity of the new compounds for DHFR derived from the various bacteria and C albicans compared with DHFR derived from rat liver is shown by PC analysis.