Design, Synthesis, and Evaluation of Thymidine Derivatives as Inhibitors of a Thymidylyltransferase Enzyme, Cps2L

Abstract

The inhibition of thymidylyltransferase enzymes has long been studied as a potential avenue for antibiotic development. Several thymidine derivatives were designed, synthesized, and evaluated for binding and inhibition against Cps2L, a thymidylyltransferase enzyme present in the bacteria Streptococcus pneumoniae. Compounds that were evaluated via WaterLOGSY binding studies indicated binding. Furthermore, most compounds demonstrated reversible inhibition, with many of those displaying Ki values within micromolar ranges. Compounds 4d and 4e bearing aldehydes, and compounds 4a and 4b bearing ortho-formylarylboronic acid pinacol esters, have the potential to covalently modify lysine residues at the active site of Cps2L. Particular potency was observed from compounds 4d and 4f; structure-activity relationship studies with these compounds may provide future directions for the iterative design of these inhibitors.