The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

Abstract

Dethiobiotin synthetase (DTBS; E.C. 6.6.6.6), thepenultimate enzyme in the biosynthesis of the essential vitaminbiotin, is a new potential target for novel herbicides. Inhibitorswere designed based on mechanistic and structural information. Thein-vitro activities of these potential inhibitors versus thebacterial enzyme are reported here. Mimics of7,8-diaminopelargonic acid (DAPA) or the DAPAcarbamate reaction intermediate were substrates or partial substratesfor the enzyme. Synergistic binding with ATP was noted with compoundswhich contained an amino functionality. NMR studies and X-raystructures confirmed that the inhibitors could be phosphorylated bythe enzyme. Several series of potential inhibitors were designed totake advantage of this partial substrate activity by generatingpotentially more tightly bound phosphorylated inhibitors in situ. Structure–activity relationships for these series based onboth substrate and inhibitory activity are described herein. AnX-ray structure for one of these inhibitors is also discussed.Although considerable potential for inhibitors of this type wasdemonstrated, none of the compounds reported showed sufficientherbicidal activity to be a commercial proposition. © 1999 Society of Chemical Industry