Synthesis and Evaluation of Fused Pyrimidines as E. coli Thymidylate Monophosphate Kinase Inhibitors

To front emergence of antibiotic resistance there is an urgent need for new therapeutics, and one seemingly relevant target is thymidylate monophosphate kinase (TMPK). Serendipitously, we discovered a naphthyl substituted pyrrolopyrimidine possessing activity towards E. coli TMPK. Based on this hit, synthesis, and screening of 61 fused pyrimidines were undertaken. The most potent derivatives were also counter assayed towards the human variant of the enzyme. Two of the inhibitors possessed promising drug-like properties and selectivity for E. coli TMPK. Although the initial pyrrolopyrimidine hit failed to have cellular activity, two alternative scaffolds were discovered providing starting points for further work.

Automated summary

A substance with activity against E. coli TMPK was discovered and led to the synthesis and screening of effective derivatives, two of which showed promising drug-like properties and selectivity for E. coli TMPK.