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.
4-Hydroxyphenylpyruvate dioxygenase
(HPPD, EC 1.13.11.27) has been
recognized as one of the most promising targets in the field of herbicide
innovation considering the severity of weed resistance currently.
In a persistent effort to develop effective HPPD-inhibiting herbicides,
a structure-guided strategy was carried out to perform the structural
optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor
scaffold first discovered in our lab. Herein, starting from the crystal
structure of Arabidopsis thaliana (At)HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione (MBQ), three subseries of quinazoline-2,4-dione
derivatives were designed and prepared by optimizing the hydrophobic
interactions between the side chain of the core structure at the R1 position and the hydrophobic pocket at the active site entrance
of AtHPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1H,3H)-dione (60) with the
best inhibitory activity against AtHPPD was identified
to be the first subnanomolar-range AtHPPD inhibitor
(K
i = 0.86 nM), which significantly outperformed
that of the lead compound MBQ (K
i = 8.2 nM). Further determination of the crystal structure
of AtHPPD in complex with compound 60 (1.85 Å) and the binding energy calculation provided a molecular
basis for the understanding of its high efficiency. Additionally,
the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1H,3H)-dione (28) and compound 60 showed acceptable crop safety against peanut and good herbicidal
activity with a broad spectrum. Moreover, compound 28 also showed superior selectivity for wheat at the dosage of 120
g ai/ha and favorable herbicidal efficacy toward the gramineous weeds
at the dosage of as low as 30 g ai/ha. We believe that compounds 28 and 60 have promising prospects as new herbicide
candidates for wheat and peanut fields.
High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the π−π sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the π−π sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors.
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