Synthesis and Evaluation of Fused Pyrimidines as E. coli Thymidylate Monophosphate Kinase Inhibitors. Issue 45 (2nd December 2021)

• Record Type: Journal Article
• Authors: Blindheim, Fredrik Heen; Malme, Ane Thoresen; Dalhus, Bjørn; Sundby, Eirik; Hoff, Bård Helge
• Is Part Of: ChemistrySelect. Volume 6:Issue 45(2021)
• Page Start: 12852
• Page End: 12857
• Publication Date: 2021-12-02
• Subjects: Antibiotics -- Nitrogen heterocycles -- Pyrrolopyrimidine -- Suzuki -- TMPK; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.202103796
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: 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. Abstract : The study presents synthesis and structure‐activity relationship of fused pyrimidines towards E. coli thymidylate monophosphate kinase (TMPK). The most potent derivative in the enzymatic assay was a pyrrolopyrimidine substituted with naphthalen‐1‐ylmethanamine at C‐4. The compound was selective for E. coli thymidylate monophosphate kinase versus the human variant of the enzyme. A few other fused pyrimidines with a ( R )‐1‐phenylethan‐1‐amine unit at C‐4 also showed promising activity.