6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3.
6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3.
复制标题
基于 6-苯胺尿嘧啶的枯草芽孢杆菌 DNA 聚合酶 III 抑制剂：基于尿嘧啶 N3 取代的抗聚合酶和抗菌结构-活性关系。
DOI：
10.1021/jm980693i
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Brown,NC
中科院分区：
文献类型：
--
作者：
TarantinoJr,PM;Zhi,C;Gambino,JJ;Wright,GE;Brown,NC
6-Anilinouracils (6-AUs) are dGTP analogues which selectively inhibit the DNA polymerase III ofBacillus subtilisand other Gram-positive bacteria. To enhance the potential of the 6-AUs as antimicrobial agents, a structure−activity relationship was developed involving substitutions of the uracil N3 position in two 6-AU platforms: 6-(3,4-trimethyleneanilino)uracil (TMAU) and 6-(3-ethyl-4-methylanilino)uracil (EMAU). Series ofN3-alkyl derivatives of both 6-AUs were synthesized and tested for their ability to inhibit purifiedB. subtilisDNA polymerase III and the growth ofB.subtilisin culture. Alkyl groups ranging in size from ethyl to hexyl enhanced the capacity of both platforms to bind to the polymerase, and with the exception of hexyl, they also significantly enhanced their antimicrobial potency. N3 substitution of the EMAU platform with more hydrophilic hydroxyalkyl and methoxyalkyl groups marginally enhanced anti-polymerase III activity but enhanced antibacterial potency severalfold. In sum, the results of these studies indicate that the ring N3 of 6-anilinouracils can tolerate substituents of considerable size and structural variety and, thus, can be manipulated to significantly enhance the antibacterial potency of this novel class of polymerase III-specific inhibitors.
