Structure-activity relationships for a new family of sulfonylurea herbicides

Abstract

Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain amino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the sulfonylurea and imidazolinone herbicides. The commercial sulfonylureas contain a pyrimidine or a triazine ring that is substituted at both meta positions, thus obeying the initial rules proposed by Levitt. Here we assess the activity of 69 monosubstituted sulfonylurea analogs and related compounds as inhibitors of pure recombinant Arabidopsis thaliana AHAS and show that disubstitution is not absolutely essential as exemplified by our novel herbicide, monosulfuron (2-nitro-N-(4'-methyl-pyrimidin-2'-yl) phenyl-sulfonylurea), which has a pyrimidine ring with a single meta substituent. A subset of these compounds was tested for herbicidal activity and it was shown that their effect in vivo correlates well with their potency in vitro as AHAS inhibitors. Three-dimensional quantitative structure-activity relationships were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. For the latter, the best result was obtained when steric, electrostatic, hydrophobic and H-bond acceptor factors were taken into consideration. The resulting fields were mapped on to the published crystal structure of the yeast enzyme and it was shown that the steric and hydrophobic fields are in good agreement with sulfonylurea-AHAS interaction geometry.

Pyrimidinylsalicylic Based Herbicides: Modeling and Prediction

“…Its respective correlation coefficient is negative indicating this electrostatic factor disfavors the inhibition. This effect is similar to that observed in the inhibition of AHAS by sulfonylurea herbicides (Wang at al., 2005), wherein the chemicals need contributions from positively charged groups to achieve enhanced inhibition, and only small areas of the active site channel of AHAS have preference for negatively charged groups. This analog trend between these two families of herbicides seems to suggest they share the same binding site in the enzyme or partially overlapping sites.…”

Exploring 2D and 3D QSARs of 2,4‐Diphenyl‐1,3‐oxazolines for Ovicidal Activity Against Tetranychus urticae

“…Zhu et al [9] have developed QSAR models with pyrazolo- [5,1-d][1,2,3,5]-tetrazin-4(3H)-one derivatives (herbicides) using physicochemical parameters in their recent study. Wang et al [10] have done CoMFA and CoMSiA studies on new family of sulfonylurea herbicides. Zou et al [11] have performed QSAR studies with a series of novel 5-[1-aryl-1,4-dihydro-6-methylpyridazin-4-one-3-yl]-2-arylamino-1,3,4-thiadiazoles (fungicides) using hydrophobicity and electronic parameters.…”

The structure–activity relationship in herbicidal monosubstituted sulfonylureas

“…The plant acetohydroxyacid synthase (AHAS) was expressed and purified as described previously 2. AHAS activity was measured by using the colorimetric assay in 50 m M potassium phosphate (pH 7.0) containing 50 m M pyruvate, 1 m M thiamine diphosphate, 10 m M MgCl 2 and 10 µ M FAD.…”