Synthesis and Herbicidal Activity of Triketone-Aminopyridines as Potent p-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

Exploring novel p-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors has become one of the most promising research directions in herbicide innovation. On the basis of our tremendous interest in exploiting more powerful HPPD inhibitors, we designed a family of benzyl-containing triketone-aminopyridines via a structure-based drug design (SBDD) strategy and then synthesized them. Among these prepared derivatives, the best active 3-hydroxy-2-(3,5,6-trichloro-4-((4-isopropylbenzyl)­amino)­picolinoyl)­cyclohex-2-en-1-one (23, IC50 = 0.047 μM) exhibited a 5.8-fold enhancement in inhibiting Arabidopsis thaliana (At) HPPD activity over that of commercial mesotrione (IC50 = 0.273 μM). The predicted docking models and calculated energy contributions of the key residues for small molecules suggested that an additional π–π stacking interaction with Phe-392 and hydrophobic contacts with Met-335 and Pro-384 were detected in AtHPPD upon the binding of the best active compound 23 compared with that of the reference mesotrione. Such a molecular mechanism and the resulting binding affinities coincide with the proposed design scheme and experimental values. It is noteworthy that inhibitors 16 (3-hydroxy-2-(3,5,6-trichloro-4-((4-chlorobenzyl)­amino)­picolinoyl)­cyclohex-2-en-1-one), 22 (3-hydroxy-2-(3,5,6-trichloro-4-((4-methylbenzyl)­amino)­picolinoyl)­cyclohex-2-en-1-one), and 23 displayed excellent greenhouse herbicidal effects at 150 g of active ingredient (ai)/ha after postemergence treatment. Furthermore, compound 16 showed superior weed-controlling efficacy against Setaria viridis (S. viridis) versus that of the positive control mesotrione at multiple test dosages (120, 60, and 30 g ai/ha). These findings imply that compound 16, as a novel lead of HPPD inhibitors, possesses great potential for application in specifically combating the malignant weed S. viridis.

Rational Redesign of Enzyme via the Combination of Quantum Mechanics/Molecular Mechanics, Molecular Dynamics, and Structural Biology Study

“…The solvation free energy (Δ G solv ) could be divided into electrostatic solvation free energy (Δ G GB ) and a nonpolar solvation free energy (Δ G np ). Furthermore, the entropic contribution was calculated following the previous work. , On the other hand, the decompose module was used to perform energy decomposition.…”

“…Furthermore, the entropic contribution was calculated following the previous work. 42,43 On the other hand, the decompose module was used to perform energy decomposition. QM/MM Calculations.…”

Survey on the Recent Advances in 4-Hydroxyphenylpyruvate Dioxygenase (HPPD) Inhibition by Diketone and Triketone Derivatives and Congeneric Compounds: Structural Analysis of HPPD/Inhibitor Complexes and Structure–Activity Relationship Considerations

“…A rational design approach based on molecular hybridization and structure-based ligand design was applied to generate additional new classes of triketone-aminopyridines as inhibitors of HPPD activity (Figure 8). 25 In the first step of design, a preliminary hit compound was generated by merging the triketone system with the tetra-substituted pyridine ring of picloram (a broad-spectrum herbicide of the auxin class). In the second step of design, molecular docking simulations suggested that the primary amino group of the hit compound could be decorated with hydrophobic appendages that were predicted to be accommodated within a hydrophobic pocket delimited by Phe392, Leu369, and Met335.…”

Novel Pyrazole Amides as Potential 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

“…As selective herbicides, 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors have attracted extensive attention because they have a unique bleaching mode of action. − These inhibitors can block the homergy of tyrosine by inhibiting the efficacy of the HPPD enzyme, which is an iron-tyrosinate protein participating in the catabolism of tyrosine, − leading to carotenoid deficiency and eventually resulting in the death of plants after presenting with the unique bleaching symptom. , Commercial HPPD inhibitors are generally classified into three broad categories (Figure ), including pyrazoles, triketones, and isoxazoles. Their common substructure is 2-benzoylethen-1-ol, which can closely chelate the ferrous ion in the active center of the HPPD enzyme to competitively inhibit the binding of p -hydroxyphenylpyruvic acid (HPPA) to ferrous ions. − Although the 2-benzoylethen-1-ol substructure can serve as the bioisostere of phenylpyruvic acid, its conservatism makes some weeds gradually develop resistance to HPPD inhibitors. , Currently, it is urgent to further diversify the substructure of HPPD inhibitors to delay the development of resistance.…”