Structure-activity relationships for a new family of sulfonylurea herbicides Jian-Guo Wang a , Zheng-Ming Li a , Ning Ma a , Bao-Lei Wang a , Lin Jiang a , Siew Siew Pang b,c , Yu-Ting Lee b , Luke W. Guddat b, * & Ronald G. Duggleby b, * a Elemento-Organic Chemistry Institute, State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, Nankai University 300071, Tianjin, P R China; b School of Molecular and Microbial Sciences, The University of Queensland, Brisbane 4072, QLD, Australia; c Novartis Institute for Tropical Diseases, 10 Biopolis Road #05–01, 138670, Chromos, Singapore Received 18 May 2005; accepted 7 November 2005 Ó Springer 2005 Key words: 3D-QSAR, acetohydroxyacid synthase, Arabidopsis thaliana, computational docking, herbi- cide, rational drug design, sulfonylurea Summary 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) phe- nyl-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. Introduction The herbicidal activity of sulfonylureas such as N- (p-cyanophenylaminocarbonyl) benzenesulfona- mide (Figure 1) was recognized nearly 40 years ago [1]. Following an extensive synthetic program led by Levitt and colleagues [2] the first modern sulfonylurea herbicide chlorsulfuron (Figure 1) was developed. Since that time, a large number of other sulfonylurea herbicides have been identi- fied and are now used widely [1]. The general features of most active compounds (Figure 1) are an ortho-substituted aromatic ring attached to the sulfur atom, and a heterocyclic ring substituted in both meta positions and attached to the distal nitrogen atom of the sulfonylurea bridge. This heterocyclic ring is either a pyrimidine (X = CH) or triazine (X = N). *To whom correspondence should be addressed. Fax: +61-7- 3365-4699; E-mail: luke.guddat@uq.edu.au; ronald.duggleby@ uq.edu.au Journal of Computer-Aided Molecular Design (2005) 19: 801–820 DOI 10.1007/s10822-005-9028-9