Structure-activity relationships for a new family of sulfonylurea herbicides.
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.
Wang
Jian-Guo
JG
Elemento-Organic Chemistry Institute, State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, Nankai University, 300071, Tianjin , PR China.
Li
Zheng-Ming
ZM
Ma
Ning
N
Wang
Bao-Lei
BL
Jiang
Lin
L
Pang
Siew Siew
SS
Lee
Yu-Ting
YT
Guddat
Luke W
LW
Duggleby
Ronald G
RG
D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry; D017360:Arabidopsis / Q000201:enzymology; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006540:Herbicides / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006540:Herbicides; D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; D000095:Acetolactate Synthase