Development of 4H-pyridopyrimidines: a class of selective bacterial protein synthesis inhibitors

Background We have identified a series of compounds that inhibit protein synthesis in bacteria. Initial IC 50 's in aminoacylation/translation (A/T) assays ranged from 3 to14 μM. This series of compounds are variations on a 5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-4-ol scaffold (e.g., 4H-pyridopyrimidine). Methods Greater than 80 analogs were prepared to investigate the structure-activity relationship (SAR). Structural modifications included changes in the central ring and substituent modifications in its periphery focusing on the 2- and 6-positions. An A/T system was used to determine IC 50 values for activity of the analogs in biochemical assays. Minimum inhibitory concentrations (MIC) were determined for each analog against cultures of Enterococcus faecalis , Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae , Staphylococcus aureus , Escherichia coli tolC mutants and E. coli modified with PMBN. Results Modifications to the 2-(pyridin-2-yl) ring resulted in complete inactivation of the compounds. However, certain modifications at the 6-position resulted in increased antimicrobial potency. The optimized compounds inhibited the growth of E. faecalis, M. catarrhalis, H. influenzae , S. pneumoniae , S. aureus , E. coli tolC , mutants and E. coli modified with PMBN with MIC values of 4, ≤ 0.12, 1, 2, 4, 1, 1 μg/ml, respectively. IC 50 values in biochemical assay were reduced to mid-nanomolar range. Conclusion 4H-pyridopyrimidine analogs demonstrate broad-spectrum inhibition of bacterial growth and modification of the compounds establishes SAR.