Identification of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as inhibitors of the phosphatase SerB653 in Porphyromonas gingivalis, implicated in periodontitis |
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Authors: | Jung Suk-Kyeong Ko Youngkyung Yu Keum Ran Kim Ju Hee Lee Joo-Youn Chae Chong Hak Ji Suk Kim Chang Hyen Lee Hyeon Kyu Choi Eun Bok Kim Bo Yeon Erikson Raymond L Chung Sang J Kim Seung Jun |
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Affiliation: | Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-Dong, Yuseong-Gu, Daejeon 305-600, Republic of Korea. |
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Abstract: | The serine phosphatase SerB653 plays a crucial role in the infection of Porphyromonas gingivalis, which contributes to the pathogenesis of periodontitis, an inflammatory disease of teeth-supporting tissues. Because functional loss of SerB653 eliminates the virulence of P. gingivalis, SerB653 inhibitors are considered potential periodontitis therapeutic or preventive agents. To identify SerB653 inhibitors with potent anti-periodontitis activity, we conducted a high-throughput screen of a representative 6800-compound subset of a synthetic chemical library of the Korea Chemical Bank (KCB) for compounds with activity against SerB653. The primary screening yielded 150 hits, and subsequent confirmatory studies identified eight compounds, mainly within a single cluster of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives, that showed greater than 50% inhibition of SerB653 activity at a concentration of 50μM. A second screening with a focused library identified 10 compounds with IC(50) values less than 10μM. In antibacterial tests, three of these compounds showed a minimum inhibitory concentration against P. gingivalis growth of 5-50nM. |
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