Quantitative structure-activity relationships of protoporphyrinogen oxidase-inhibiting diphenyl ether herbicides

Abstract

Diphenyl ether (DPE) herbicides induce protoporphyrin IX (Proto IX) accumulation in plants by inhibiting the enzyme protoporphyrinogen oxidase (Protox). Others have shown DPE herbicides to inhibit Protox competitively with respect to its substrate, protoporphyrinogen IX (Protogen). We compared the geometrical, bulk, and electronic parameters of Protogen and the DPE acifluorfen. Our analysis suggests that a competitive inhibitor of Protox must be bicyclic, representing roughly one half fraction of Protogen, for fulfilling the steric complementarity. We also examined the relationships between molecular properties of 24 DPE herbicides and their effects on enzyme-inhibitory and herbicidal activities in barley ( Hordeum vulgare L.) and cucumber ( Cucumis sativus L.). All compounds inhibited Protox although their I 50 values ranged from 0.008 to 420 μ M. The QSAR involving 24 DPEs showed that (a) the electronic (partial charge, S LUMO, and dipole moment) and lipophilicity properties accounted for the variation in the Protox-inhibiting activity and (b) the molecular bulk and overall electrostatic potentials were responsible for the observed variation in the herbicidal effects. In general, the analogues with substitutions on the m-carbon of the p-nitrophenyl ring were highly active as both enzyme-inhibitors and herbicides. Neither the enzyme-inhibitory activity nor the initial herbicidal activity were changed by substituting a p-chloro for a p-nitro group. In the acifluorfen-methyl structure, the herbicidal activity was completely lost when the CF 3 group was moved from the para to the meta position. Compounds with sulfide, sulfoxide, or sulfone bridges between the phenyl rings were herbicidally inactive.