Pyrazole–Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC 50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1Hpyrazole-4-carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a K i value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (K i = 44 nM) and slightly more potent than mesotrione (K i = 4.56 nM). In addition, the cocrystal structure of the AtHPPD−4ae complex was successfully resolved at a resolution of 1.8 Å. The Xray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π−π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.

Cytological Effects of Herbicidal and Fungicidal Pesticides on Root Apex Meristem Cells of Triticum Aestivum

“…In proteins stacking interactions between aromatic amino acid residues also play an important role in maintaining the stability of their 3D structure. The ability of pesticide molecules to participate in the formation of stacking interactions implies their ability to form protein adducts and DNA adducts, and, as a result, to exhibit cyto-and genotoxicity [30,31,32,33,34,35,36,37].…”

Discovery of novel arylthioacetic acid derivatives as 4‐hydroxyphenylpyruvate dioxygenase inhibitors

“…The post-emergent herbicidal activities were determined according to a previously reported procedure. 14,[17][18][19][20][22][23][24][25][26][27] Abutilon juncea (AJ), Eclipta prostrata (EP), Amaranthus retroflexus (AR), Echinochloa crus-galli (EC), Setaria faberii (SF), and Digitaria sanguinalis (DS) were chosen to evaluate the synthesized compounds. The commercial herbicide mesotrione was selected as positive control.…”

“…Soybean, canola, cotton, corn, rice, and wheat were selected and underwent crop safety testing. [26][27][28][29] The commercial herbicide mesotrione was selected as a positive control. Of the tested crops, proximately 20 seeds (bud rate ≥ 85%) were sown in composite nutrient soil at a depth of 2 cm and grown at a temperature of 15 to 30°C in a glasshouse.…”

“…13 Studies over the past decades have provided important information on interactions between HPPD enzymes and HPPD inhibitors: 1,3-dicarbonyl and aromatic moieties are an indispensable pharmacophore for potent HPPD inhibition. Many researches [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] in HPPD inhibitors indicated that modification of the aromatic moieties is an effective way to get new derivatives with excellent weed control.…”

Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors

“…In recent years, crops severely suffer from infestations of various weeds, and the weeds resistance are increasing seriously [ 1 ]. The development of novel green herbicides with highly efficient, eco-friendly, high crop selectivity while low toxicity has become urgent [ 2 , 3 , 4 ].…”