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

Joseph W Guiles,Andras Toro,James M Bullard,Urs A Ochsner

doi:10.1186/2191-2858-2-5

Abstract

BackgroundWe 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).MethodsGreater 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.ResultsModifications 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.Conclusion4H-pyridopyrimidine analogs demonstrate broad-spectrum inhibition of bacterial growth and modification of the compounds establishes SAR.

Highlights

We have identified a series of compounds that inhibit protein synthesis in bacteria
The optimized compounds inhibited the growth of E. faecalis, M. catarrhalis, H. influenzae, S. pneumoniae, S. aureus, E. coli tolC, mutants and E
IC50 values in biochemical assay were reduced to mid-nanomolar range

Summary

Introduction

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 to μM. This series of compounds are variations on a. Bacterial infections continue to represent a major worldwide health hazard. Our health care systems are increasingly confronted with drug-resistant hospital and community-acquired infections [1]. With the recent emergence of numerous, clinically important, drug-resistant bacteria including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Mycobacterium tuberculosis, enhanced-spectrum b-lactamase producing. The majority of clinically important antibiotics target the ribosome. Full list of author information is available at the end of the article and protein synthesis in general [2,3] and most of these are naturally occurring antibiotics or derivatives of naturally occurring antibiotics [4,5].

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Conclusion