Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase

► B. anthracis DHFR is effectively inhibited by dihydrophthalazine inhibitors. ► Derivations at the chiral center of these inhibitors markedly affect the potency. ► Enzyme and whole cell inhibition and crystallography indicate best derivations. ► In silico calculations highlight role of enantiomeric energy differences. ► Potency is maximized with S-phenyl or S-isobutenyl groups on the phthalazine.