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Structure‐activity optimization of 4H‐pyridopyrimidines: a class of selective bacterial protein synthesis inhibitors
Author(s) -
Bullard James M,
Guiles Joseph W.,
Toro Andras,
Ochsner Urs
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.967.1
Subject(s) - escherichia coli , chemistry , antibacterial activity , protein biosynthesis , minimum inhibitory concentration , biochemistry , bacteria , in vitro , biology , gene , genetics
Bacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. Previous screening of a focused chemical compound library using a polyU mRNA‐directed aminoacylation/translation protein synthesis system from Escherichia coli yielded a lead series of compounds that inhibit protein synthesis with IC 50 's ranging from 3 to14 μM (Ribble, et. al. (2010) AAC , 54, 4648–4657). This series of compounds all contained the same central scaffold composed of tetrahydropyrido[4,3‐ d ]pyrimidin‐4‐ol (e.g. 4H‐pyridopyrimidine). These compounds inhibited bacterial growth with minimum inhibitory concentrations (MICs) ranging from 0.25 to 32 μg/ml. Results Over 100 analogs of the initial compounds were designed and synthesized and assayed. In biochemical protein synthesis reactions nineteen of the compounds exhibited IC 50 values less than 2.0 μM and seven less than 1.0 μM. These compounds were active against S. pneumoniae (MIC=2 μg/mL), H. influenzae (MIC=1 μg/mL), and M. catarrhalis (MIC≤0.12 μg/mL) and S. aureus (4= μg/ml). Macromolecular synthesis (MMS) assays in E. coli and S. aureus confirmed that antibacterial activity resulted from specific inhibition of protein synthesis. Conclusion Optimization of 4H‐pyridopyrimidines yields potent inhibitors of protein synthesis with good activity against respiratory pathogens.