Synthesis, herbicidal activity, crop selectivity, and in silico study of some new pyrazole-4-one derivatives

Abstract

Targeting 4-hydroxyphenylpyruvate dioxygenase (HPPD) is a validated strategy for developing postemergence herbicides. In this work, nine new pyrazole-4-one derivatives L1-L9 were designed and synthesized through a prodrug approach based on the commercial HPPD inhibitor topramezone, wherein the isoxazole ring was opened and the phenolic hydroxyl group was converted into various ester and ether functionalities. Post-emergence herbicidal evaluation against six weed species revealed that compounds L5 and L6 exhibited excellent activity against dicotyledonous weeds, with L5 achieving 100% control of Chenopodium serotinum at 150 g a.i./ha, slightly surpassing topramezone (95%). Notably, crop selectivity assays demonstrated that L5 and L6 are safe for maize, wheat, and rice, causing negligible or even negative fresh weight inhibition, in contrast to topramezone, which severely damaged wheat and rice. Molecular docking with the Arabidopsis thaliana HPPD crystal structure (Protein Data Bank: 1TFZ) confirmed that the active intermediate 9b binds tightly to the enzyme active site through a five-coordinate complex and additional hydrogen bonds, rationalizing the observed efficacy. In silico absorption, distribution, metabolism, excretion, and toxicity predictions indicated that both L5 and topramezone are non-inhibitors of CYP2D6, non-mutagenic, and biodegradable. Density functional theory calculations at the B3LYP/6-31G(d,p) level revealed that L5 possesses a highest occupied molecular orbital-lowest unoccupied molecular orbital gap of 4.23 eV and an electrophilicity index of 4.15, compared to 3.99 eV and 4.49 for topramezone, reflecting distinct electronic properties consistent with its prodrug design. Collectively, these results validate the prodrug strategy for enhancing crop selectivity and identify L5 and L6 as promising lead candidates for further development as selective herbicides in rice, wheat, and maize cultivation.. KEYWORDS :Pyrazolyl ketone derivatives, 4-Hydroxyphenylpyruvate dioxygenase herbicides, Herbicidal activity, Docking.