THE DESIGN AND SYNTHESIS OF INHIBITORS OF IMIDAZOLEGLYCEROL PHOSPHATEDEHYDRATASE AS POTENTIAL HERBICIDES

The discovery and exploration of a new class of broad-spectrum posteme rgent herbicides with a novel mode of action, namely the disruption of histidine biosynthesis via inhibition of imidazoleglycerol phosphate dehydratase (IGPD; E.C.4.2.1.19), are described. Clear structural simi larities between the first member, produced during an attempt to produ ce analogues of glyphosate, and intermediates in histidine biosynthesi s were noted. Several series of targets were designed, to mimic both t he enzyme substrate and a putative reaction intermediate, and synthesi sed. Some examples were found to be both extremely potent inhibitors o f the enzyme, having K-i values as low as 0.3 nM, and phloem-mobile he rbicides with levels of weed control similar to those shown by glyphos ate. Further logical progress awaits a high-resolution X-ray structure determination of an enzyme-inhibitor complex.