Synthesis Of Novel Pyrazole Derivatives And Study Of Their Herbicidal Activit

Weeds cause serious harm to agricultural production,resulting in crop yield and quality of agricultural products.4-Hydroxyphenylpyruvate dioxygenase（HPPD）is an important target for the development of novel herbicides.HPPD inhibitors can hinder photosynthesis and induce weed death with bleaching symptoms.Pyrazole HPPD inhibitors have been widely used in the creation of new herbicides due to their abundant substitution sites and diverse substituents.In this paper,a series of novel pyrazole A and B derivatives containing acylhydrazones and amino acids were designed and synthesized based on active substructure splicing principle and the introduction of herbicidal active pharmacophore such as acylhydrazone and amino acid into the fourth position of pyrazole ring while retaining the core pyrazole ring.The work of this paper is summarized as follows:1.A total of fifty novel pyrazole compounds were designed and synthesized,and their structures were characterized by ¹H NMR,¹³C NMR,HRMS and X-ray single crystal diffraction.2.The herbicidal activity and crop safety of target compounds were determined by Petri dish assays.The results showed that most of the compounds had excellent inhibitory effect on the growth of broad-leaved weeds.Compounds B2,B7,B13 and B16 had 100%inhibition on the growth of Portulaca oleracea at the dose of 100μg/m L.Compounds B2 and B7 also showed good inhibitory activities against Amaranthus tricolor with 100%inhibition rates,which were significantly better than the positive controls glyphosate and topramezone.While compared with glyphosate and topramezone,most of the compounds showed higher safety to crops.3.The in vitro inhibitory activities of these compounds on HPPD were determined.The results showed that the compounds had good inhibitory effects on HPPD,and their IC₅₀ values ranged from 0.04μM to 0.10μM,which was better than topramezone(IC₅₀value was 0.11μM).Compounds B5,B10 and B24 showed the best inhibitory activity with IC₅₀ values of 0.04μM,0.06μM and 0.07μM,respectively.4.Molecular docking studies were conducted to elucidate the inhibitory effect of these compounds on HPPD activity through hydrophobicπ-πinteraction and strong hydrogen action.For example,compounds A6,B5 and B7 can form hydrophobicπ-πorπ-alkyl interactions with amino acid residues Phe360 and Phe403 at the active site.Meanwhile,compounds A6,B5 and B7 can interact with the carbonyl group of Gln286through strong hydrophilic hydrogen bond.Compounds B5 and B7 can form hydrogen bonds with Asn261 and Ser246.In addition,molecular dynamics simulations and microscale thermophoresis measurement showed that compounds could bind closely to HPPD.