Pocket-Oriented Design of Benzene-Fused Pyridinecarboxylates as Potent Synthetic Auxin Herbicides

Abstract Synthetic auxin herbicides (SAHs) with pyridinecarboxylate scaffolds are valued for their high efficacy and favorable safety, yet their limited structural diversity has constrained further development. In this study, we analyzed sequence variations in TIR1/AFBs among different species and employed a pocket-oriented molecular design strategy to synthesize pyridinecarboxylate derivatives bearing novel benzene-fused six-membered ring frameworks. Through systematic structural optimization, we identified compound 8o, which showed outstanding herbicidal activity against many weeds at 3.75 g ai/ha and high crop safety at 30 g ai/ha. What’s more, the interaction between protein AFB5 and IAA was stronger in the presence of compound 8o (Kd = 0.97 μM) than that with clopyralid (Kd = 7.20 μM) or halauxifen-methyl (Kd = 3.96 μM). Molecular simulations suggested that this enhanced activity may arise from a T−π interaction between 8o and Phe127. These results suggest that naphthyl rings as promising frameworks for the development of next-generation SAHs.