Pyrazolidine-3,5-dione-based inhibitors of phosphoenolpyruvate carboxylase as a new class of potential C4 plant herbicides

Abstract

Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme in the C₄ photosynthetic pathway of many of the world's worst weeds and a valuable target to develop C₄ plant-selective herbicides. By virtual screening, analog synthesis, and in vitro validation, we identified pyrazolidine-3,5-diones as a new class of small molecules with inhibitory potential down to the submicromolar range against C₄ PEPC and a selectivity factor of up to 16 over C₃ PEPC. No other biological activity has yet been reported for the best compound, (3-bromophenyl)-4-(3-hydroxybenzylidene)-pyrazolidine-3,5-dione. A systematic variation in the substituents allowed the derivation of a qualitative structure-activity relationship. These findings make this compound class highly interesting for further investigations toward generating potent, C₄ plant-selective herbicides with a low potential for unwanted effects.

Keywords: C4 photosynthesis; phosphoenolpyruvate; pyrazolidine-3, 5-diones; selective C4 herbicides; virtual screening.