Abstract

Background

We have identified a series of compounds that inhibit protein synthesis in bacteria. Initial IC₅₀'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 IC₅₀ 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. IC₅₀ 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.

Keywords:

antibiotic; drug discovery; structure-activity relationship (SAR); protein synthesis; inhibitor; Staphylococcus aureus; Streptococcus pneumoniae