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

Markus Dick; German Erlenkamp; Giang T T Nguyen; Kerstin Förster; Georg Groth; Holger Gohlke

doi:10.1002/1873-3468.12842

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

FEBS Lett. 2017 Oct;591(20):3369-3377. doi: 10.1002/1873-3468.12842. Epub 2017 Sep 24.

Authors

Markus Dick¹, German Erlenkamp¹, Giang T T Nguyen², Kerstin Förster², Georg Groth², Holger Gohlke¹

Affiliations

¹ Institute of Pharmaceutical and Medicinal Chemistry and Bioeconomy Science Center (BioSC), Heinrich-Heine-Universität Düsseldorf, Germany.
² Institute of Biochemical Plant Physiology and Bioeconomy Science Center (BioSC), Heinrich-Heine-Universität Düsseldorf, Germany.

PMID: 28889573
DOI: 10.1002/1873-3468.12842

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.

Publication types

Letter

MeSH terms

Asteraceae / drug effects
Asteraceae / enzymology
Asteraceae / growth & development
Cloning, Molecular
Drug Design
Enzyme Assays
Escherichia coli / genetics
Escherichia coli / metabolism
Gene Expression
Herbicides / chemical synthesis
Herbicides / chemistry*
Herbicides / pharmacology
High-Throughput Screening Assays
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Isoenzymes / genetics
Isoenzymes / metabolism
Molecular Docking Simulation
Phosphoenolpyruvate Carboxylase / antagonists & inhibitors*
Phosphoenolpyruvate Carboxylase / chemistry
Phosphoenolpyruvate Carboxylase / genetics
Phosphoenolpyruvate Carboxylase / metabolism
Photosynthesis / drug effects
Plant Proteins / antagonists & inhibitors*
Plant Proteins / chemistry
Plant Proteins / genetics
Plant Proteins / metabolism
Plant Weeds / drug effects
Plant Weeds / enzymology
Plant Weeds / growth & development
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Structure-Activity Relationship
User-Computer Interface

Substances

Herbicides
Isoenzymes
Plant Proteins
Pyrazoles
Recombinant Fusion Proteins
pyrazolidine-3,5-dione
Phosphoenolpyruvate Carboxylase

Associated data

PDB/3ZGE
PDB/3ZGB