Design, synthesis and biological evaluation of novel N-nitrophenyl derivatives based on the structure of acetohydroxyacid synthase

Abstract

Acetohydroxyacid synthase (AHAS, EC: 2.2.1.6) is a target for the development of novel herbicides. Two series of N-nitrophenyl derivatives, type-A and type-B, were designed and synthesized based on the active site of the AHAS structure. All the structures of newly prepared compounds were thorough characterized by IR, and ¹H NMR spectrums. The IC₅₀ values of all synthesized target compounds against AHAS enzyme and EC₅₀ values for herbicidal activity against Brassica campestris L., Amaranthus mangostanus L. and Sorghum sudanense were determined. The bioactive assay results showed that the type-B compounds exhibited highly improved inhibitory activity against the AHAS enzyme and the tested plants comparing to type-A compounds. The IC₅₀ values of most type-B compounds against the AHAS enzyme were between 25-177μM. The EC₅₀ values of several type-B compounds against Sorghum sudanense reached 5.0mg/L. The differences in the biological activity between type-A and type-B compounds were attributed to two structural features - the orthogonal bend at the N-nitro amides group and the common plane structure of another phenyl with chain bridge. With the structure of the target compounds and the IC₅₀ values for AHAS enzyme, a statistically significant CoMFA model with high predict abilities (q²=0.606, r²=0.982, N=4, SEE=0.058, F=280.255) was obtained, and its reliability was verified. The model will provide a theoretical basis for the further structural optimization.

Keywords: AHAS; Herbicide; Inhibitors; QSAR; Synthesis.