Identification of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4-one derivatives as inhibitors of the phosphatase SerB653 in Porphyromonas gingivalis, implicated in periodontitis.
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.
Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-Dong, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
Suk-Kyeong
SK
Jung
Youngkyung
Y
Ko
Keum Ran
KR
Yu
Ju Hee
JH
Kim
Joo-Youn
JY
Lee
Chong Hak
CH
Chae
Suk
S
Ji
Chang Hyen
CH
Kim
Hyeon Kyu
HK
Lee
Eun Bok
EB
Choi
Bo Yeon
BY
Kim
Raymond L
RL
Erikson
Sang J
SJ
Chung
Seung Jun
SJ
Kim
D016866:Bacteroidaceae Infections / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010518:Periodontitis / Q000188:drug therapy / Q000382:microbiology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C544515:1,4-dihydroquinoline; D004791:Enzyme Inhibitors; D011804:Quinolines; D010744:Phosphoric Monoester Hydrolases