鉴定5,6-二氢咪唑并[2,1-b]噻唑为一类新型抗菌剂。
Identification of 5,6-dihydroimidazo[2,1-b]thiazoles as a new class of antimicrobial agents.
作者信息
Li Yangmei, Bionda Nina, Fleeman Renee, Wang Hongjie, Ozawa Akihiko, Houghten Richard A, Shaw Lindsey
机构信息
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States.
出版信息
Bioorg Med Chem. 2016 Nov 1;24(21):5633-5638. doi: 10.1016/j.bmc.2016.09.027. Epub 2016 Sep 12.
In an effort to develop novel antimicrobial agents against drug-resistant bacterial infections, 5,6-dihydroimidazo[2,1-b]thiazole compounds were synthesized and tested for their antimicrobial activity. Eight compounds comprised by two sub-scaffolds were identified as hits against methicillin-resistant Staphylococcus aureus (MRSA). These hits were modified at 6-position by replacing (S)-6 to (R)-6 configuration and the (R)-isomers increased their antimicrobial activities by two-fold. The most active compound showed a MIC value of 3.7μg/mL against MRSA in a standard microdilution bacterial growth inhibitory assay. This compound protected wax moth worms against MRSA at a dose of 5× MIC using a worm infectious model. This compound also exhibited inhibition of DNA gyrase activity in a DNA gyrase supercoil assay, suggesting the 5,6-dihydroimidazo[2,1-b]thiazoles may target DNA gyrase for the antimicrobial action.
为了开发针对耐药细菌感染的新型抗菌剂，合成了5,6-二氢咪唑并[2,1-b]噻唑化合物，并测试了它们的抗菌活性。由两个子支架组成的八种化合物被鉴定为对耐甲氧西林金黄色葡萄球菌（MRSA）有活性。通过将（S）-6构型替换为（R）-6构型，这些活性化合物在6位进行了修饰，并且（R）-异构体的抗菌活性提高了两倍。在标准微量稀释细菌生长抑制试验中，最具活性的化合物对MRSA的MIC值为3.7μg/mL。使用蠕虫感染模型，该化合物以5×MIC的剂量保护蜡螟幼虫免受MRSA感染。在DNA回旋酶超螺旋试验中，该化合物还表现出对DNA回旋酶活性的抑制作用，表明5,6-二氢咪唑并[2,1-b]噻唑可能以DNA回旋酶为抗菌作用靶点。
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