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

Dethiobiotin synthetase (DTBS;E.C. 6.6.6.6), the penultimate enzyme in the biosynthesis of the essential vitamin biotin, is a new potential target for novel herbicides. Inhibitors were designed based on mechanistic and struct ural information. The in-vitro activities of these potential inhibitors ver sus the bacterial enzyme are reported here. Mimics of 7,8-diaminopelargonic acid (DAPA) or the DAPA carbamate reaction intermediate were substrates or partial substrates for the enzyme. Synergistic binding with ATP was noted with compounds which contained an amino functionality, NMR studies and X-ra y structures confirmed that the inhibitors could be phosphorylated by the e nzyme. Several series of potential inhibitors were designed to take advanta ge of this partial substrate activity by generating potentially more tightl y bound phosphorylated inhibitors in situ, Structure-activity relationships for these series based on both substrate and inhibitory activity are descr ibed herein. An X-ray structure for one of these inhibitors is also discuss ed. Although considerable potential for inhibitors of this type was demonst rated, none of the compounds reported showed sufficient herbicidal activity to be a commercial proposition. (C) 1999 Society of Chemical Industry.