Structure-based ligand design and discovery of novel tenuazonic acid derivatives with high herbicidal activity

INTRODUCTION: Computer-aided design has become an important tool to develop novel pesticides based on natural lead compounds. Tenuazonic acid (TeA), a typical representative of the natural tetramic acid family, was patented as a potential bioherbicide. However, its herbicidal efficacy is still not up to the ideal standard of commercial products. OBJECTIVES: We aim to find new TeA’s derivatives with improved potency. METHODS: Molecular docking was used to build ligand-acceptor interaction models, design and screen new derivatives. Phytotoxicity, oxygen evolution rate, chlorophyll fluorescence and herbicidal efficacy were determined to estimate biological activity of compounds. RESULTS: With the aid of a constructed molecular model of natural lead molecule TeA binding to the Q(B) site in Arabidopsis D1 protein, a series of derivatives differing in the alkyl side chain were designed and ranked according to free energies. All compounds are stabilized by hydrogen bonding interactions between their carbonyl oxygen O2 and D1-Gly256 residue; moreover, hydrogen bond distance is the most important factor for maintaining high binding affinity. Among 54 newly designed derivatives, D6, D13 and D27 with better affinities than TeA were screened out and synthesized to evaluate their photosynthetic inhibitory activity and herbicidal efficacy. Analysis of structure-activity relationship indicated that D6 and D13 with sec-pentyl and sec-hexyl side chains, respectively, were about twice more inhibitory of PSII activity and effective as herbicide than TeA with a sec-butyl side chain. CONCLUSION: D6 and D13 are promising compounds to develop TeA-derived novel PSII herbicides with superior performance.