Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils.
Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils.
复制标题
3-取代-6-(3-乙基-4-甲基苯胺基)尿嘧啶的合成和抗菌活性。
DOI：
10.1021/jm050517r
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Storer,Richard
中科院分区：
文献类型：
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作者：
Zhi,Chengxin;Long,Zheng-yu;Manikowski,Andrzej;Brown,NealC;TarantinoJr,PaulM;Holm,Karsten;Dix,EdwardJ;Wright,GeorgeE;Foster,KimA;Butler,MichelleM;LaMarr,WilliamA;Skow,DonnaJ;Motorina,Irina;Lamothe,Serge;Storer,Richard
Numerous 3-substituted-6-(3-ethyl-4-methylanilino)uracils (EMAU) have been synthesized and screened for their capacity to inhibit the replication-specific bacterial DNA polymerase IIIC (pol IIIC) and the growth of Gram+ bacteria in culture. Direct alkylation of 2-methoxy-6-amino-4-pyrimidone produced the N3-substituted derivatives, which were separated from the byproduct 4-alkoxy analogues. The N3-substituted derivatives were heated with a mixture of 3-ethyl-4-methylaniline and its hydrochloride to effect displacement of the 6-amino group and simultaneous demethylation of the 2-methoxy group to yield target compounds in good yields. Certain intermediates, e.g. the 3-(iodoalkyl) compounds, were converted to a variety of (3-substituted-alkyl)-EMAUs by displacement. Most compounds were potent competitive inhibitors of pol IIIC (Kis 0.02−0.5 μM), and those with neutral, moderately polar 3-substituents had potent antibacterial activity against Gram+ organisms in culture (MICs 0.125−10 μg/mL). Several compounds protected mice from lethal intraperitoneal (ip) infections withS.aureus (Smith) when given by the ip route. A water soluble derivative, 3-(4-morpholinylbutyl)-EMAU hydrochloride, given subcutaneously, prolonged the life of infected mice in a dose dependent manner.
