Review

pubs.acs.org/JAFC

4‑Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals † † † † ‡ Ferdinand Ndikuryayo, Behrooz Moosavi, Wen-Chao Yang,*, and Guang-Fu Yang*, , † Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30071, P. R. China

ABSTRACT: The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4- hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions. KEYWORDS: 4-hydroxyphenylpyruvate dioxygenase, chemical biology, inhibitor, agrochemical, herbicide

■ INTRODUCTION The world confronts widespread food scarcity due to several factors, including the increase in global population, the reduction of arable land, and the proliferation of weeds. To combat these weeds, farmers have resorted to various strategies, such as crop rotation, tilling, and usage of herbicides. However, new challenges, such as weed resistance,1 herbicide toxicity,2,3 low crop selectivity,4 and high cost of discovery, production, and registration of herbicides,5 have been raised over the years. Therefore, there is still a serious need to design potent, Figure 1. Coupled enzyme reaction used for the evaluation of the selective, environmentally friendly and cost-effective herbicides, activity of HPPD and its inhibitors. (A) The conversion of 4- which can limit a broad range of weeds as well as their resistant hydroxyphenylpyruvate dioxygenase (HPPD) into homogentisic acid biotypes. (HGA) and (B) the transformation of HGA into maleylacetoacetate For this purpose, 4-hydroxyphenylpyruvate dioxygenase is (MAA). one of the most important target enzymes.6 Naturally occurring assembling relevant knowledge. Our purpose is not to Downloaded via HUAZHONG NORMAL UNIV on January 19, 2019 at 08:36:44 (UTC). in all aerobic organisms apart from some Gram-positive bacteria,7,8 HPPD catalyzes the conversion of 4-hydroxyphe- summarize all the current literature, but to propose more See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. nylpyruvic acid (HPPA) into homogentisic acid (HGA) comprehensive knowledge based on recent reports that (Figure 1A) in the tyrosine degradation pathway.9 The study provided valuable information for the exploration of novel of this pathway, which resulted in the development of several HPPD inhibitors. We emphasized HPPD structure and commercial HPPD-inhibiting herbicides (Table 1), engendered functions, chemistry (catalytic and inhibitory mechanisms), substantial research for pharmaceutical and agrochemical discovery and development of HPPD-inhibiting herbicides, and profits. The conclusions showed that HPPD-inhibiting strategies to genetically engineer resistant crops. In addition, we herbicides have many benefits, such as broad-spectrum activity raised some relevant gaps for future research directions in this against broadleaf weeds including those resistant to other area. herbicides, excellent crop selectivity, low application rate, low 10−14 ■ THE BIOLOGICAL ROLE OF HPPD toxicity, and a pre- and postemergence treatment. ff In humans, HPPD dysregulation is associated with the type I Although the toxicological e ects of these herbicides on the 16 17 ecosystem have not been investigated thoroughly, developers tyrosinemia, type III tyrosinemia, and hawkinsinuria. In and farmers seem to agree on their weed control efficacy.15 However, the current knowledge on various aspects of Received: August 18, 2017 HPPD inhibitors is still scattered and hence more clarification Revised: September 7, 2017 is required for the end users, i.e., researchers and farmers. Accepted: September 14, 2017 Therefore, we prepared this review with the intention of Published: September 14, 2017

© 2017 American Chemical Society 8523 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

a Table 1. Most Representative Commercial HPPD-Based Herbicides

market size USD class % (millions) ingredient year company crop controlled weed application triketones 4.4 1,283 tefuryltrione 2010 Bayer CropScience rice annual and perennial postemergent tembotrione 2007 Bayer Crop Science corn broadleaf postemergent mesotrione 2001 Syngenta corn broadleaf pre/ postemergent bicyclopyrone 2015b Syngenta corn annual and broadleaf pre/ postemergent sulcotrione 1991 ICI corn broadleaf postemergent benzobycyclon 2001 SDS Biotech rice broadleaf pre/ postemergent isoxazoles 0.9 255 isoxaflutole 1998b Bayer Crop Science corn, sugar cane broadleaf pre-emergent 2013c soybean pyrazoles 1.3 374 benzofenap 1987 Mitsubishi rice annual and perennial pre/ Chemical broadleaf postemergent pyrasulfotole 2008 Bayer Crop Science wheat, barley, broadleaf postemergent triticale pyrazoxyfen 1985 Ishihara rice annual and perennial pre/ broadleaf postemergent pyrazolynate 1980 Sankyo rice annual and perennial pre/ postemergent topramezone 2006 BASF corn annual and broadleaf postemergent aThis table was constructed on the basis of previous publications.5,77,85 bEPA registration. cApproved by Animal and Plant Health Inspection Service (APHIS). microorganisms, the enzyme confers virulence to many pathogens due to the production of melanins.18 Dahnhardt et al.19 demonstrated that the disturbance of Synechocystis HPPD encoding gene, which has a high homology to plant gene, results in the shortage of tocopherol biosynthesis. In plants, HPPD is a physiological imperative for typical growth.20 Indeed, its product, HGA, is converted into plastoquinone-9, the essential component of carotenoid biosynthesis,20 and tocopherols (Figure 2). These compounds prevent plants from high-light, cold, drought, and salt stresses.21,22 Therefore, the inhibition of the HPPD-catalyzed reaction, which occurs in − chloroplasts,23 leads to photosynthetic impairment11 14,24 25 Figure 2. Biosynthesis of tocopherols and plastoquinone-9 in plants. followed by leaf bleaching. Dashed arrows represent multiple steps. Homogentisate phytyltrans- ferase (HPT) catalyzes the combination of homogentisic acid (HGA) ■ THE STRUCTURE OF HPPD and phytyldiphosphate (PDP), a chlorophyll byproduct, leading to 2- methyl-6-phytyl-BQ (MPBQ), which, in turn, is methylated to 2,3- During more than 30 years of investigation, knowledge about dimethyl-6-phytyl-1,4-benzoquinol (DMPBQ) by MPBQ methyltrans- HPPD has advanced with technology, including X-ray ferase (MPBQ MT). HGA interacts with geranylgeranyl diphosphate crystallography and bioinformatics. Consequently, HPPD (GGDP) to yield 2-methyl-6-geranylgeranyl-1,4-benzoquinol structures have been determined, uploaded, and stored in (MGGBQ), which is consecutively methylated into 2,3-dimethyl-5- protein data banks, where they are accessible either as primary geranylgeranyl benzoquinol (DMGGBQ) by MPBQ MT. All HGA structures (Table 2) or as three-dimensional (3D) structures products undergo a tocopherol cyclase (TC)-catalyzed reaction γ δ α (Table 3). resulting in - and -tocopherols that are then converted into - and − β γ γ With a subunit mass between 36 and 50 kDa,26 28 HPPD has -tocopherols by -tocopherol methyltransferase ( -TMT). Abbrevia- tions: TAT, tyrosine aminotransferase; PD, prephenate dehydrogen- a primary structure that comprises two major domains: the fl ase; HPPA, 4-hydroxyphenylpyruvate acid; HPPD, 4-hydroxyphenyl- exible N-terminus and the conserved C-terminus that contains pyruvate dioxygenase; HST, homogentisate solanesyltransferase; PK, 29−31 the active site. In plants, the extension of at least 30 phytol kinase; CHLase, chlorophyllase; MSBQ, 2-methyl-6-solanesyl- residues contributes to a substantial irregularity at the N- 1,4-benzoquinol; PDP, phytyl diphosphate; SDP, solanesyl diphos- 32 terminus with respect to mammalian and bacterial enzymes. A phate; DXP, 1-deoxy-D-xylulose-5-phosphate; GGDP, geranylgeranyl remarkable distinction in plant HPPDs is the inclusion in the diphosphate; HGGT, homogentisate geranylgeranyltransferase; last half of the primary structure of a supplementary disordered MGGBQ, 2-methyl-6-geranylgeranyl-1,4-benzoquinol; DMGGBQ, 2,3-dimethyl-5-geranylgeranyl benzoquinol. This figure was con- 15-residue segment close to comparatively unvarying C- − structed on the basis of previous publications.67,102 112 terminus.16,32,33 This segment, whose removal is associated with the reduction of the reaction speed without affecting the substrate binding,16 has been observed to adopt multiple conformations in the presence or absence of ligands.34 Whether with these additional residues is still vague, and more or not the specific activities of HPPD inhibitors are associated investigation may reveal their catalytic role.

8524 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Table 2. Reviewed Primary Sequences of HPPD Stored in structural similarity among HPPDs. The comparison of UniProtKB secondary structures shows that residues are generally made α β a of -helices and -sheets at the rate of around 27% and 31%, entry entry name organism length respectively. Also, the analysis of the 3D structures of HPPDs P32754 HPPD_HUMAN Homo sapiens 393 stored in the Protein Data Bank (RCSB PDB37) shows that all P32755 HPPD_RAT Rattus norvegicus 393 HPPDs share the same 2-His-1-Glu facial triad (Figure 3), P93836 HPPD_ARATH Arabidopsis thaliana 445 which is always connected to β-strands and binds to Fe(II). P49429 HPPD_MOUSE Mus musculus 393 However, the location of the residues engaged in the facial triad O52791 HMAS_AMYOR Amycolatopsis orientalis 357 is dependent on the source of HPPD. Another fundamental Q02110 HPPD_PIG Sus scrofa 393 difference among HPPD structures is that bacterial HPPDs P80064 HPPD_PSEUJ Pseudomonas sp. 357 function as tetramers, whereas plant and mammalian HPPDs Q53586 HPPD_STRAW Streptomyces avermitilis 381 function as dimers, respectively.27,28,32 Q5EA20 HPPD_BOVIN Bos taurus 393 To understand the HPPD chemistry, 3D structures have Q5ZT84 LLY_LEGPH Legionella pneumophila 348 considerably served the computational studies in the process of Q76NV5 HPPD_DICDI Dictyostelium discoideum 367 herbicide design. Interestingly, the corresponding predictions Q6TGZ5 HPPD_DANRE Danio rerio 397 mostly correlate with experimental data and hence provide P69053 LLY_LEGPC Legionella pneumophila 348 valuable insights into how substrate and inhibitor compete for − Q22633 HPPD_CAEEL Caenorhabditis elegans 393 the active site.11 14 It is noteworthy to mention that, like many Q5BKL0 HPPD_XENTR Xenopus tropicalis 394 enzymes, the point mutations of conserved residues signifi- Q60Y65 HPPD_CAEBR Caenorhabditis briggsae 393 cantly affect the activity of HPPD (Table 4).7,38,39 O23920 HPPD_DAUCA Daucus carota 442 Q27203 HPPD_TETTH Tetrahymena thermophila 404 ■ ENZYME ACTIVITY AND ASSAY O48604 HPPD_HORVU Hordeum vulgare 434 E9CWP5 HPPD_COCPS Coccidioides posadasii 399 It is required to carefully determine the enzyme activity with a Q4WHU1 HPPD1_ASPFU Neosartorya fumigata 403 reliable assay prior to subsequent analyses, i.e., mechanistic and Q1E803 HPPD_COCIM Coccidioides immitis 399 inhibitory studies. For this purpose, the most common early Q9ARF9 HPPD_PLESU Plectranthus scutellarioides 436 stage consists in determination of optimal reaction conditions according to the method of choice. Therefore, a basic reaction P0CW94 HPPD_COCP7 Coccidioides posadasii 399 2+ Q9S2F4 HPPD_STRCO Streptomyces coelicolor 381 mixture mainly comprises HPPD, HPPA, Fe , and reductant for which reduced 2,6-dichlorophenolindophenol or ascorbate Q9I576 HPPD_PSEAE Pseudomonas aeruginosa 357 ff 27 O42764 HPPD_ZYMTR Zymoseptoria tritici 419 are almost equally e ective. Moreover, glutathione can be added to block a nonenzymatic decarboxylation during Q6CDR5 HPPD_YARLI Yarrowia lipolytica 394 27 Q557J8 HPDL_DICDI Dictyostelium discoideum 494 incubation. More interestingly, in the absence of HPPA, the Q8K248 HPDL_MOUSE Mus musculus 371 natural substrate of HPPD, the addition of L-tyrosine, the Q96IR7 HPDL_HUMAN Homo sapiens 371 precursor of HPPA, to the bacterial culture permits the Q96X22 HPPD_MAGO7 Magnaporthe oryzae 419 determination of the enzyme activity. This is possible because Q5XIH9 HPDL_RAT Rattus norvegicus 371 Escherichia coli contains endogenous transaminases trans- forming L-tyrosine into HPPA, which, in turn, is catalyzed by Q872T7 HPPD_NEUCR Neurospora crassa 412 31 Q4WPV8 HPPD2_ASPFU Neosartorya fumigata 406 the recombinant HPPD. P23996 MELA_SHECO Shewanella colwelliana 346 To evaluate the enzyme activity, various methods relying on the measurement of the changes in reagents or products have O06695 VLLY_VIBVU Vibrio vulnificus 357 40 Q55810 Y090_SYNY3 Synechocystis sp. 339 been developed. For example, Lindblad determined the 14 14 Q18347 YBWL_CAEEL Caenorhabditis elegans 364 activity of HPPD by following the release of CO2 from C- labeled HPPA or the formation of HGA. On the basis of the aThese structures were downloaded from the UniProt Web site.36 reaction depicted in Figure 1, conventional methods were developed such as the measurement of the volume of fi 38,41 42 While many authors agree that the C-terminus ful lls the consumed O2 and produced CO2, liquid chromatography, catalytic capability of HPPD, Norris et al.20 showed that the mass spectrometry,43 fluorescence,44 and tandem mass removal of 17-bp in the N-terminal domain of HPPD gene in spectrometry.45 An easy and rapid method might be either Arabidopsis thaliana gives rise to the complete loss of its the spectrophotometric measurement of the production of activity. Subsequently, Tomoeda et al.17 demonstrated that HGA or the consumption of HPPA, but these potential patients suffering from hawkinsinurea had an A33T mutation in methods are unsuitable because these compounds have a close the HPPD-coding gene although the actual cause was later UV absorption. Fortunately, resorting to a supplementary established to be associated with N241S variant.35 Moreover, enzyme, homogentisate 1,2-dioxidase (HGD), enabled the the addition of Ala18−Asn33 peptide to Phe34−Glu435, which measurement of HPPD activity based on a coupled enzyme initially yielded insoluble protein, enabled the recovery of both reaction46 (Figure 1) in which the final product, maleylacetoa- solubility and activity of maize HPPD variant.32 Although the cetate (MAA), has an intense absorption in the range of 300− corresponding catalytic mechanism has remained unclear so far, 350 nm.47 This indirect measurement has many advantages as the previous findings have suggested that the N-terminal follows: (i) both HPPD- and HGD-catalyzed reactions can take sequence may considerably influence the enzyme functionality, place in the same reaction system, which is widely used for the despite its poor homology. evaluation of the activity of both HPPD and its inhib- − Using the Clustal Omega program,36 multiple sequence itors;11 14,48 (ii) it is user-friendly; and (iii) it enables a high- alignment of 39 reviewed HPPD sequences (Table 2) revealed throughput screening that greatly saves time and minimizes 32 conserved and 60 similar residues, suggesting a high experimental errors. Recently, Rocaboy-Faquet et al.49 have

8525 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Table 3. Current HPPD Three Dimensional Structures Stored in Protein Data Bank

PDB entrya resolution (Å) released date source chain(s) ligand ref 5CTO 2.62 7/24/2015 Arabidopsis thaliana A, B, C, D NTBC 68 1T47 2.5 6/15/2004 Streptomyces avermitilis A, B, C, D NTBC 29 1CJX 2.4 4/26/2000 Pseudomonas fluorescens A, B, C, D 30 1TFZ 1.8 8/17/2004 Arabidopsis thaliana A DAS869 47 1TG5 1.9 8/17/2004 Arabidopsis thaliana A DAS645 47 1SP9 3.0 9/21/2004 Arabidopsis thaliana A, B 32 1SQD 1.8 8/17/2004 Arabidopsis thaliana A 47 1SQI 2.15 8/17/2004 Rattus noregicus A DAS869 47 3ISQ 1.75 9/15/2009 H. Sapiens A 113 5HMQ 2.37 10/19/2016 Pseudomonas putida A, B, C 114 5DHW 2.62 09/07/2016 Arabidopsis thaliana A,B sulcotrione 115 5EC3 2.1 11/18/2015 Homo sapiens A 116 1SP8 2.0 09/21/2004 Zea mays A, B, C, D 32 5XGK 2.6 not yet Arabidopsis thaliana A, B, C, D HPPA b aThese 3D structures, which were obtained by X-ray diffraction, are downloaded from the Protein Data Bank (RCSB PDB37). bVery recently deposited by Yang, G. F., Yang, W. C., and Lin, H. Y. Crystal structure of Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD) complexed with its substrate 4-hydroxyphenylpyruvate acid (HPPA) (Deposition ID: 1300003469). Except 5XGK, only inhibitors are presented as ligands (Figure 9) in complex with HPPD.

the inhibition parameters, IC50 and Ki, represent the activity of its inhibitors. It has been shown that the previous HPPD characteristics are species dependent (Table 4). ■ THE EXPRESSION OF RECOMBINANT HPPD In the course of the development of HPPD inhibitors, recombinant HPPDs are essentially required to be expressed sufficiently. To this end, laborious techniques ranging from gene identification to protein purification are carefully performed to produce sufficient quantities of recombinant HPPD. In general, the coding gene from the organism of interest is inserted onto a plasmid that, in turn, is transformed into different bacterial strains (usually E. coli BL21 strain). The Figure 3. Crystal structure of Arabodopsis thaliana HPPD (AtHPPD) HPPD gene is under the control of an inducible promoter complexed with sulcotrione (yellow). The facial triad (green) binds to which allows HPPD overexpression. The HPPD gene from Fe(II). The picture was drawn by PyMol software (Version 1.8 various species should be specifically chosen and assessed since Schrödinger, LLC) based on 5DHW deposited in Protein Data Bank the behavior of each enzyme is species dependent (Table 4). by Yang, W. C., and Yang, G. F. Crystal structure of AtHPPD Arabidopsis thaliana is commonly used as a biological model for complexed with sulcotrione. Unpublished results. weeds.12,50 Although the utilization of strains whose growing medium has been adjusted for high level protein expression Table 4. Kinetic Parameters of Some Wild Type (WT) and precludes the requirement for further optimization of specific Mutants of Recombinant Carrot and Human HPPD strains,51 studies have pointed out that the same strain may ff HPPD enzyme K (μM) k (S1−) ref grow distinctly under di erent conditions, e.g., temperature and m cat incubation time.12,52,53 Consequently, the most suitable carrot WT 1.8 7.5 ± 25 38 conditions should be determined for new enzyme and plasmid Q372E 7.5 286 ± 22 to optimize the amount and activity of the recombinant HPPD. Q300E 2.1 551 ± 76 ± Q286E 0.1 452 63 ■ THE CATALYTIC MECHANISM N275D 0.2 153 ± 32 S260A 0.3 9 ± 3 The catalytic mechanism of HPPD has been extensively human WT 200 3.3 ± 0.4 39 investigated. Various studies have been carried out using a H183A 90 0.16 ± 0.004 combination of structural, spectroscopic, pre-steady state H266A 180 0.13 ± 0.01 kinetic, and theoretical computations. The conclusions of E349G 100 0.05 ± 0.002 these studies led to agreements on some common steps. For E349Q 200 0.4 ± 0.1 example, HPPD chemistry is similar to that of other α-keto acid-dependent oxygenases (α-KAOs) in which the addition of substrate is ordered. Also, in the HPPA to HGA conversion developed an easy and cost-effective colorimetric method based reaction, HPPD receives electrons from the α-keto acid of the on the release of a melanin-like pigment that is repressed by the pyruvate substituent of HPPA, yielding decarboxylated and presence of HPPD inhibitor in bacterial culture media. hydroxylated products.16 The data obtained from the However, the activity of HPPD is commonly assessed by combination of site-directed mutagenesis and computational measuring the kinetic parameters, Vmax, Km, and kcat, whereas calculations have revealed the interactions between the

8526 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Figure 4. Simplified catalytic mechanism of HPPD: (1) formation of HPPD−HPPA complex; (2) dioxygen addition; (3) decarboxylation; (4) O−O cleavage; (5) acetic acid chain migration; (6) C1 hydroxylation. substrate or intermediates and key residues in the active site. MM calculations based on the crystal structure of AtHPPD Although the HPPD chemistry governing the catalytic cycle (PDB entry: 1SQD) and carrot HPPD, Raspail et al.38 recently remains unknown, we summarize the relevant and current confirmed this hypothesis. Indeed, the authors demonstrated knowledge as depicted in Figure 4. that Gln358 binds to the carboxylate moiety of HPPA, whereas The Formation of HPPD−HPPA Complex. In the resting Gln272 and Gln286 attach the 4-hydroxy group. This state of HPPD, Fe(II) has an octahedral ligand field conclusion was confirmed by Huang et al.39 in human arrangements with three water molecules in coordination site HPPD. In addition, Raspail et al.38 have concluded that the fi 16,29,30,38 not lled by the facial triad (Figure 3) that fasten the hydrogen bond is weakened in the Q286E variant whereas Km 39 fi Fe(II) into the active site for catalysis. HPPA can then bind to and kcat remain unchanged in native HPPD. This nding HPPD−Fe(II) under anaerobic conditions, and a charge highlights not only the implication of glutamine residue in the transfer commences when the α-keto acid part contacts the formation of the complex through hydrogen bonding via 4- Fe(II) with bidentate coordination.54 Consequently, two water hydroxy group but also its role in the first nucleophilic attack by molecules are relocated and thereby the HPPD−Fe(II)−HPPA oxygen. complex retains six-coordinate geometry55 in which HPPA Dioxygen Addition. While the resting enzyme has only a presumably binds to Fe(II) through its carboxylate group.39 slight tendency to oxidize in the presence of dioxygen, the first Using the quantum mechanics/molecular mechanics (QM/ nucleophilic attacker, the enzyme−substrate complex, has high MM) and molecular modeling, the interaction between HPPA molecular oxygen reactivity, which is associated with the and the active site of Arabidopsis thaliana HPPD (AtHPPD) complex planarity.38 This configuration augments the electron was investigated. This study led to the hypothesis that the facial density at the metal and hence activates the reduction of 38 16,38,56 triad might stabilize the substrate even though their dioxygen. This changing reactivity of Fe(II) toward O2 in substitution resulted in decreased enzyme activity.39 Therefore, the presence of HPPA, which is an effector for the enzyme to much attention has been returned to the binding mode of 4- reduce dioxygen, is proposed as the starting point for the 9,16 hydroxy group of the substrate, and multiple hypotheses have ordered addition of O2 and HPPA. The carboxylate group of been formulated. For example, Brownlee et al.29 suggested the HPPA may also be critically involved in the activation of the involvement of 4-hydroxy group in π-stacking interactions with dioxygen, the early and key step for oxygenase activity.57 the rings of two conserved phenylalanine residues, whereas Although a 5-coordination iron center may be available for O2 Serre et al.30 hypothesized its connection to conserved binding,58 a recent report showed that this geometry is not a glutamine residues through hydrogen bonding. Using QM/ conditional requirement for increased dioxygen reactivity.55

8527 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Decarboxylation and O−O Cleavage. The dioxygen addition to HPPD−Fe(II)−HPPA complex results in quintet − − 2−• iron dioxygen species, Fe(III) O , in which CO2 molecule is very lightly bound to iron and readily detached from the active site.33,59,60 The decarboxylation produces Fe(III)− peracid species whose O−O bond is cleaved, leading to activated oxygen species.33 Fe(II) is then transformed into Fe(IV) due to the presence of two negatively charged ligands in the iron coordination shell.16,33 This assumption was confirmed in AtHPPD where conserved residues (Asn261 and Ser246) Figure 5. Chemical structures of some compounds involved in the properly orient the HPPA intermediate for the Fe(IV)−oxene early discovery of HPPD inhibitors: 1, 2-(3-methylbutanoyl)- electrophilic attack at the aromatic C1.7,28,38 However, clear cyclohexane-1,3,5-trione (leptospermone); 2, 3-hydroxy-2-(2- functions of individual residues and the means by which the phenoxyacetyl)cyclohex-2-enone; 3,1,1′-(3,7,9-trihydroxy-8,9b-di- enzymes orchestrate the catalytic cycles are largely unknown.16 methyl-1-oxo-1,9b-dihydrodibenzo[b,d]furan-2,6-diyl)diethanone Fe(IV)−Oxene Electrophilic Attack at the Aromatic (usnic acid); 4, 2-(2-chlorobenzoyl)-5,5-dimethylcyclohexane-1,3- fl Ring. Subsequently, the iron double-bonded oxygen binds to dione; 5, 2-chloro-4-(tri uoromethyl)benzoic acid. the ring C1,17,16 leading to an epoxide that is the first intermediate in the native HPPD-catalyzed reaction.16 To diversity of HPPD inhibitors has given rise to relative activities explain this predilection to C1 in HPPA, Borowsky et al.33 due to their various structures that may influence their compared the activation energies at C1 and C2. The results chemistry. For example, DAS869 is a potent inhibitor of both showed high activation energy at C2 due to electronic effects, plant and mammalian HPPDs, whereas DAS645 is highly conferring the specificity to HPPD toward HPPA. However, selective for plant enzymes.47 Moreover, HPPD inhibitors tend Shah et al.61 stated that other pathways, such as a benzylic to undergo a tautomerization reaction to form enols in aqueous cation pathway, could take place in variant forms of HPPD. solution.66 Acetic Acid Side-Chain Migration and C1 Hydrox- The investigation of the interaction between DAS645 and ylation. The transformation of Fe(IV)−oxene leads to the AtHPPD (PDB entry: 1TG5) led to the conclusion that the formation of a bond between oxygen and C1 atom, which triketone moiety can form a bidentate interaction with Fe(II) in implies the lowest energy barrier.33 The rupture of epoxide ring the active site.12,48,67 Another interaction, π−π interaction, was results in products that are not immediately involved in the found between the quinoline motif and Phe360 and Phe403.11 catalytic reaction but possibly released into the solution by A similar conclusion, which was supported by other reports,13,24 HPPD variants due to the lack of native product specificity.7 was also drawn from the study of the interactions between 2 For instance, arene is not considered as a catalytic intermediate and AtHPPD (PDB entry: 5CTO).13,68 While Fe(II) since it is suggested to be neither directly formed from oxene coordination is accomplished by the usual facial triad, the nor a necessary intermediate.33 During this critical step, Raspail remaining coordinating water molecules are substituted by the et al.38 demonstrated that 4-hydroxy group of the intermediate β-keto−enol system from the inhibitor. The loading and maintains the interactions with Asn261 and Ser246 residues accommodation of the inhibitor, which requires a diketone through hydrogen bonding network by acting as acceptor and moiety to mimic the α-keto acid group of the substrate,13,65,69 donor, respectively. The rupture of epoxide ring then are fulfilled by phenylalanine residues.47 commences the displacement of acetic acid side chain to the In the HPPD−Fe(II)−inhibitor complex, the inhibitor neighboring carbon through NIH shift.62 However, although interacts uniquely with Fe(II) prior to oxidization into this shift was believed to be unique to HPPD activity, it has Fe(III).70 It is noteworthy that no hydrogen bonds or ionic been shown that it can be catalyzed by an unrelated enzyme.38 interactions participate in the complex but van der Waals At present, no definitive data support the mechanism by which contacts.16 The conclusions from kinetic studies stated that this catalysis occurs. The ring recovers its aromatic character inhibitors, triketones in particular, bind progressively to the through a tautomerization reaction in which a proton transfer, catalytic site and compete with HPPA over time,11,65,71,72 self C1 hydroxylation, takes place from the C2 carbon to the leading to irreversibility.73 However, Ellis et al.74 have observed ketone oxygen.33 Clearly, the residue Ser246 of AtHPPD is a 90% recovery of the HPPD inhibitor activity from crude rat essential for this step.38 Finally, HPPD undergoes rate-limiting cytosol over 10 h after inhibition, initiating a slow dissociation conformational changes and proton movement during HGA of the inhibitor from HPPD−Fe(II)−inhibitor complex. The release that leave the active site unable to reconnect to the investigation of inhibitory reactions becomes more complicated product.63 Interestingly, this reaction can take place in solution when the inhibitor binds only to one site. For instance, Garcia where it can enable the kinetic study of HPPD-catalyzed et al.73 have concluded that the binding of diketonitile, the reaction in vitro. degradation product of isoxaflutole, to one catalytic site of dimeric carrot HPPD results in a nonlinear consumption of O2. ■ INHIBITORY MECHANISM Despite their importance to medicine and agriculture, how such The research on HPPD inhibitors for clinical and agricultural inhibitors interact with HPPD is still largely unclear, and further purposes increased with the observation that leptospermone 1 investigation is necessary. (Figure 5), the natural HPPD inhibitor secreted by Callistemon citrinus L., had the capability of inhibiting the growth of the ■ THE DISCOVERY AND DEVELOPMENT OF HPPD surrounding grasses.64,65 Consequently, several HPPD inhib- INHIBITORS itors were designed and synthesized on the basis of this HPPD can be inhibited either by natural products such as observation. However, a solid understanding of their inhibitory leptospermone 1,15,64 usnic acid 3,65 and benzoquinones75 or mechanism of the inhibitors was lacking. Unlike HPPA, the synthetic compounds (Figure 5).12,15,50 Since leptospermone

8528 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Figure 6. Iterative process of the discovery and development of HPPD-based herbicides.

Table 5. Postemergent Crop Selectivity of Selected Compounds at Dose Rate of 150 g ai/ha

AtHPPD inhibn inhibn (%) a b μ compd Ki ( M) maize soybean rice wheat cotton canola ref 15 0.012 ± 0.006 5 10 0 0 5 0 14 16 0.055 ± 0.030 0 2.5 0 0 17.5 0 mesotrione 0.013 ± 0.001 0 60 0 0 65 95 14 0.189 ± 0.040 2.5 50 40 80 100 10 13 mesotrione 0.013 ± 0.001 0 55 50 40 80 100 9 0.032 ± 0.001 0 60 50 0 50 nd 12 10 0.005 ± 0.001 10 75 20 85 60 nd mesotrione 0.013 ± 0.001 10 55 50 40 70 nd 11 0.009 ± 0.001 5 30 40 30 40 80 11 12 0.017 ± 0.001 0 25 0 0 20 55 13 0.035 ± 0.007 0 30 30 20 40 80 mesotrione 0.013 ± 0.001 10 55 50 40 70 100 a b Chemical structures of the compounds are given in Figures 8 and 9. Ki, inhibition constant of the enzyme reaction. For mesotrione, it is a mean value calculated from different data. was found to possess the basic requisite characteristics for in then, intensive investigation was undertaken particularly in vivo herbicidal activity,76 these compounds were subjected to favor of triketones and led to the development and launch of structural optimization for commercial use.52 Subsequently, the the corn HPPD herbicides (sulcotrione and mesotrione).77 In first two HPPD inhibitors, pyrazolinate and pyrazoxyphen, were the late 1980s, the optimization of 5 led to isofluxatole, developed in the early 1970s and 1985, respectively.77 Both establishing a new class of HPPD inhibitors containing an turned out to be prodrugs because they released the free isoxazole heterocycle.77 HPPD inhibitors belonging to this class hydroxypyrazole that bound to and inhibited the HPPD are also prodrugs, because they are rapidly degraded in soil and enzyme. In 1982, 4 was discovered as the first active triketone- plants to the corresponding diketonitriles, which exhibit a good type HPPD inhibitor with unique bleaching symptoms.25 Since herbicidal activity.78,79 Intensive and laborious work has

8529 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Figure 7. Some typical structures of patented HPPD inhibitors by Sygenta (A), Nippon Soda (B), Nissan (C), and BASF (D). followed and resulted in commercial HPPD-based herbicides data, due to the complexity of the HPPD-catalyzed reaction, the (Table 1). diversity of HPPD inhibitors, and the plant metabolic As depicted in Figure 6, with the computer-aided ligand specificity.25,38,83 Therefore, the synthetic lead compounds are design approach, both ligand- and target-based virtual screening usually subjected to in vitro and in vivo screening to verify the are currently used to identify HPPD inhibitor candidates. To activity of the HPPD inhibitor candidates and their harmful this end, the correlation between their biological activities and effects on the ecosystem.84 Following this process has enabled 3D forms at the molecular level are mostly calculated using a various companies to design and develop a large number of − comparative molecular field analysis (CoMFA).80 82 A typical active compounds including those patented,85 of which some example is the discovery of novel HPPD inhibitors on the basis examples are given in Table 5. To date, three main classes of of receptor-based virtual screening that was more effective in commercial HPPD inhibitors are known, namely, izoxazoles, detecting novel chemical scaffolds.81 For example, the docking pyrazoles, and triketones.77 of 151,047 small molecules into the active site of AtHPPD Based on the structure−activity relationship (SAR), an (PDB entry: 1TFZ) has shown the interactions between increased number of emerging compounds with commercial hydrophobic groups and certain amino acids. Using the potential have been discovered (Figure 7).85 Recently, valuable HipHop model, only four lead compounds (ratio of 1:37762) efforts have been focused on triketones, in particular those of were finally identified with potential inhibitory effects.81 This Wang and collaborators.12,13,48 They have demonstrated that approach has significantly reduced the time and cost required the introduction of 6 onto the benzoyl moiety of triketone for the discovery and development of HPPD inhibitors. Indeed, motif could be utilized as an innovative lead structure for it provides a clear and solid insight into how HPPD and herbicide discovery.48 Interestingly, compound 7 was two times inhibitors interact, the basis on which potential inhibitors can more potent than mesotrione, a commercial HPPD-based be designed. Therefore, this approach provides guidelines that herbicide, whereas compound 8 showed more than 85% will greatly contribute to designing novel and more effective inhibition against four tested weeds, even at a low dose rate of HPPD-inhibiting herbicides. 37.5 g ai/ha. More interestingly, the same compound was also However, the expected inhibitory activities of in silico safe for both rice and wheat by postemergent application at a validated compounds do not always match with the in vivo high rate. Likewise, the substitution of 6 at the N-1 position

8530 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

Figure 8. Some lead compounds with the most potential for commercial HPPD-based herbicides. (A) The schematic approach of Wang et al.12,13,48 and chemical scaffolds. (B) Other lead compounds. Dashed arrows represent multiple steps.

Figure 9. Chemical structures of common commercial HPPD inhibitors. Some of them (fourth row) are used as ligands in current 3D structures. resulted in compounds 9 and 10. It is noteworthy that these al.14 obtained compounds 14 and 15 that displayed not only a compounds show a strong broad-spectrum and postemergent good herbicidal activity but also an effective winter broadleaf herbicidal activity in maize and wheat, even at a low dose rate of weed control. 37.5 g ai/ha.12 To search for new HPPD inhibitors, Yang et This series of experiments resulted in two important al.12 designed and optimized the triketone−quinoline hybrids compounds, Y13161 and Y13287 (Figure 9), that demonstrated (Figure 8) and concluded that compound 11 might be a an excellent herbicidal activity, very much comparable to that of promising herbicide for maize fields whereas compound 12 was mesotrione, in corn field. Interestingly, Y13161 demonstrated found to be selective to maize, rice, and wheat. For the first an excellent herbicidal activity and crop safety in sorghum field, time, in addition to its safety to maize, compound 13 was whereas the mesotrione showed similar herbicidal activity but discovered to be safe to canola.13 Hence it might have the with high phytotoxicity. Due to its great commercial potential, potential to be exploited as a postemergence herbicide for weed Y13161 is undergoing new pesticide registration in China as a control in maize and canola fields. At the same time, Yang et selective herbicide for sorghum production. This is particularly

8531 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review important, because currently there is no HPPD-inhibiting For example, the substitution of the benzoyl moiety led to the herbicide for weed control in sorghum field. Recently, the conclusion that the electron-withdrawing substituents are an crystal structure of AtHPPD complexed with Y13161 (not unquestionable requirement for the herbicidal activity due to an shown) was obtained. increased acidity of the molecule.11,13,25,77 This statement is also applicable to the quinoline ring of 11 and 9 analogues.11,12 ■ THE STRUCTURE−ACTIVITY RELATIONSHIPS OF Moreover, the introduction of methylthio and methoxy groups HPPD INHIBITORS at the 1,3-cyclohexane ring considerably increased the The Structure−Activity Relationships of Natural herbicidal activity of 11 analogues by increasing their uptake 11 Products. Recombinant AtHPPD is very sensitive to β- in plants. However, positioning the aryl-containing sub- triketones, but less sensitive to benzoquinones, naphthoqui- stituents on the same ring reduced the activity presumably due 12 nones, and anthraquinones. Moreover, triketone natural to steric hindrance. The same effect was observed at the 1,3- products were known to act as competitive tight-binding cyclohexane ring of 11 analogues on which successive 11 inhibitors, whereas the others did not appear to bind tightly to methylation led to the loss of activity. While the substitution HPPD. In vitro investigations revealed that their inhibitory with para-nitro groups on the benzoyl moiety was not fruitful, activity is largely associated with the chemical structure. ostensibly due to their susceptibility to reduction in plants and Subsequently, it was demonstrated that the position of soil, their replacement by para-methylsulfonyl group showed a saturated side chain, high steric hindrance, asymmetry, high herbicidal activity. Interestingly, ortho-nitro analogues molecular planarity, enantiomer, and higher lipophilicity of were consistently active compared to their ortho-chloro 25 13 alkyl chain could influence the enzyme activity.52 These analogue counterparts. However, Wang et al. found that findings were later confirmed by Dayan et al.,80 who showed more powerful electron-withdrawing groups on the benzene that the introduction of C9 alkyl side chain to β-triketone ring were detrimental to herbicidal activity due to increased resulted in a 13-fold increase in inhibitory activity compared metabolism once absorbed by plants. with sulcotrione. The dione moiety was investigated for its implication in crop The Structure−Activity Relationships of Pyrazole and selectivity. The conclusions of this study stated that the Its Hybrids. On the basis of in vivo SAR studies of pyrazoles, addition of substituents to the cyclohexanedione can block the 11,12,71 Witschel75 suggested that the combination of the chelating sites of metabolism by plants, resulting in greater motif N−O with CO should be remarkably promising for the herbicidal activity as the plants have greater difficulty in 87,88 development of HPPD inhibitors belonging to the class of detoxifying the molecule. Although the potential of pyrazoles. In addition, a SAR study of pyrazole−benzimidazo- herbicidal activity is more significant in grass than in broadleaf lone hybrids has been recently published86 and revealed that species, the cyclohexanedione ring substitution can effect a loss 71 the generic chemical structure of these compounds can be of maize selectivity and increase soil persistence. Therefore, broken down into pyrazole ring and benzimidazolone (Figure unsubstituted cyclohexanediones are preferred. Of note, the 10A). The introduction of methyl group at the 3-position of reported in vitro and in vivo data sometimes lead to contradictory conclusions about SAR. This ambiguity may be due to the poor understanding of the HPPD-catalyzed reaction, the diversity of HPPD inhibitors, and the plant metabolic specificity.25,38 ■ THE FATE AND EFFECTS OF HPPD INHIBITORS ON THE ECOSYSTEM Traditional pesticides have been blamed to have hazardous impact on the ecosystem. To minimize the impact, some new synthetic and marketed pesticides evolved from natural products. After a long application, agrochemicals can either remain in the soil under their native state or undergo the − Figure 10. Structure−activity relationship of HPPD inhibitors. (A) degradation process.88 90 In the case of HPPD inhibiting Pyrazole−benzimidazolone hybrid: inhibitory activity decreases when herbicides, a few available reports have pointed out that some − R1 = CH3 and decreases when R3 = big substituent. (B) Synthetic commercial grade products and their metabolites, if they exist, triketones: electron-withdrawing substituents on benzoyl moiety and can have toxic effects toward living organisms.91 Fortunately, substitution of the cyclohexanedione on the dione moiety increase the biological activity. some available studies have shown that technical grade products are not harmful,92 suggesting that the observed toxicity may be due to either additional compounds in the pyrazole ring resulted in a decreased biological activity due to course of formulation or metabolites. For example, Chaima et stronger hindrance between the compounds and the active site. al.93 demonstrated that sulcotrione could induce cell stress in On the other hand, the increased size of substituent on the R3 Vicia faba. This stress, which was amplified by the addition of position of the benzimidazolone moiety led to reduced activity compounds, might be followed by cell death. Consequently, the due to steric hindrance.86 interaction of herbicides may change the biological properties The Structure−Activity Relationships of Synthetic of herbicide. By exposing the microorganisms Tetrahymena Triketones. The SAR of triketones is the most investigated pyriformis and Vibrio fischeri to mesotrione, sulcotrione, and framework for developing HPPD inhibitors. They share the their metabolites (Figure 11), Bonnet et al.91 concluded that same template that can be broken into the benzoyl and dione products 17, 18, 19, and 20 have a greater toxicity than their parts (Figure 10B); each one appears to play distinct roles in parent molecules. Given that herbicide active ingredients are the overall expression of herbicidal activity and crop selectivity. rarely used alone in commercial formulations, it is more

8532 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

of new herbicides and (ii) extend the utilization of HPPD-based herbicides to other crops.10 Although few weed species are resistant to HPPD herbicides yet, this resistance is expected to have a considerable impact in the next decade regarding the potential of HPPD herbicides.83,96,99 Therefore, with the purpose of taking advantages of these promising herbicides, experimental attempts have been focused on three main strategies (Figure 12). HPPD Overproduction. This strategy consists of three steps as follows: (i) identification of relevant residues engaged in the active site; (ii) modification of the target gene, i.e., Figure 11. Molecular structures of the degradation products of HPPD; and (iii) transformation of the plant by the plasmid sulcotrione: 17, 1,3-cyclohexanedione; 18, 2-chloro-4-methylsulfonyl- harboring the modified gene followed by its overexpression in benzoic acid; 19, 2-amino-4-methylsulfonylbenzoic acid; and 20,4- the target plant which has already exhibited a low resistance to a methylsulfonyl-2-nitrobenzoic acid. given HPPD-based herbicide. The first successful transgenic crops were made in 1996 by Sailland et al.100 by cloning and appropriate to test the single compounds as well as the mixture, expressing the modified Pseudomonas fluorescens HPPD and that is because the toxicity of a molecule usually depends (Pf HPPD) gene in tobacco, maize, and soybean. The resulting on the metabolites91 and the biological model.94 transgenic plants exhibited a high resistance to isoxaflutole compared with their wild counterparts. More recently, Siehl et ■ TRANSGENIC CROPS RESISTANT TO HPPD al.4 achieved field tolerance in transgenic soybean plants to the INHIBITORS HPPD-inhibiting herbicides mesotrione, isoxaflutole, and Selective herbicides control specific weed species, while leaving tembotrione. the desired crop unharmed. Unfortunately, most marketed HPPD Bypass. As depicted in Figure 12A, this strategy herbicides control only certain types of weeds while the number relies on the synthesis of HGA independent of HPPD. For this of resistant species is increasing.1 This situation signals a need purpose, three exogenous genes are introduced into the usual for new effective herbicides and traits. In 1996, the commercial HPPD-catalyzed pathway: first, HPPO from Arthrobacter glyphosate-resistant crops, namely, soybean, corn, cotton, and globiformis, which encodes the hydroxyphenylpyruvate oxidase canola, have been proved to be easy to use, effective, (HPPO, EC 1.2.3.13) and transforms HPPA into 2-(4- economical, and more environmentally friendly than the hydroxyphenyl)acetic acid (4-HPA); second and third, HPAH nonengineered crops whichwerereplacedbythem.91,95 and HPAC from Pseudomonas acidovorans, which encode 4- Based on their advantages,8,12,15 HPPD-inhibiting herbicides HPA hydroxylase (HPAH) and 4-HPA catalase (HPAC), have potential to be successfully used against weeds in the fields respectively. These enzymes catalyze the two-step conversion of of tolerant crops in which they are rapidly degraded.71,73 4-HPA into HGA. Because the product of each of the previous However, two cases of resistance to mesotrione, tembotrione, three genes is insensitive to HPPD inhibitors,10 their and topramezone mainly used in maize and soybean fields were overexpression in a target crop should significantly increase reported in Amaranthus tuberculatus in Illinois96 and Iowa97 in its resistance toward these herbicides. 2009. Recently, two additional HPPD-inhibiting herbicides The Increase of HPPA Expression in Plants. This (pyrasulfotole and isoxaflutole) have been reported in corn, strategy relies on the hypothesis that the inhibitor and HPPA sorghum, and soybean,98 suggesting a need for development of may compete for the active site.10 Therefore, more substrate new weed management strategies. molecules may prevent the inhibitor from binding and hence As for glyphosate, the recourse to engineered HPPD- enable the production of higher amounts of HGA, leading to inhibitor resistant crops is preferred because they can (i) the production of more indispensable substances for plant minimize the cost allocated to the discovery and development growth.20 The technique refers to the metabolism of shikimate

Figure 12. Strategies for development of transgenic crops tolerant to HPPD inhibitors: (A) HPPD bypass; (B) increase of HPPA for the competition with the inhibitor to the active site of HPPD.

8533 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537 Journal of Agricultural and Food Chemistry Review

(Figure 12B) in which the phenylalanine and tyrosine pathways *E-mail: [email protected]. Tel: 86-27-67867706. separate only at arogenate in most plants. Theoretically, it Fax: 86-27-67867141. seemed plausible to increase the HPPA amount by bypassing its ORCID synthesis at the prephenate level. However, the major challenge Wen-Chao Yang: 0000-0002-6722-0441 turned out to be the natural and irreversible transmission of the Guang-Fu Yang: 0000-0003-4384-2593 plant prephenate into arogenate, which is converted into tyrosine by arogenate dehydrogenase. Fortunately, these Funding reactions are reversed in yeasts and E. coli in which prephenate This work was funded by the National Key R&D Program dehydrogenase transforms prephenate into HPPA, which is in (2017YFD0200507) and National Natural Science Foundation turn transaminated into tyrosine.10 Consequently, the over- of China (No. 21332004, 21672079 and 21372093). expression of the yeast prephenate dehydrogenase (PDH) (EC Notes 1.3.1.43) in tobacco resulted in a nearly 40- to 60-fold increase The authors declare no competing financial interest. in resistance with respect to wild-type plants.101 ■ REFERENCES ■ IMPLICATIONS (1) Sparks, T. C.; Nauen, R. IRAC: Mode of action classification and insecticide resistance management. Pestic. Biochem. 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Also, the investigation activity of novel quinazoline-2,4-diones as 4-hydroxyphenylpyruvate 2015 − of the structure−activity relationships of other main classes of dioxygenase inhibitors. Pest Manage. Sci. , 71, 1122 1132. (13) Wang, D.-W.; Lin, H.-Y.; He, B.; Wu, F.-X.; Chen, T.; Chen, Q.; HPPD inhibitors, such as pyrazoles and izoxazoles, would be a Yang, W.-C.; Yang, G.-F. An efficient one-pot synthesis of 2- valuable contribution. (aryloxyacetyl)cyclohexane-1,3-diones as herbicidal 4-hydroxyphenyl- pyruvate dioxygenase inhibitors. J. Agric. Food Chem. 2016, 64, 8986− ■ AUTHOR INFORMATION 8993. (14) Yang, W.-C.; Xu, Y.-L.; Lin, H.-Y.; Wu, Y.; Yang, G.-F. Design, Corresponding Authors synthesis and bioevaluation of benzothiadiazole-containing pyrazoles *E-mail: [email protected]. Tel: 86-27-67867800. Fax: as novel HPPD inhibitors. Zhongguo Kexue: Huaxue 2016, 46, 1180− 86-27-67867141. 1187.

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8537 DOI: 10.1021/acs.jafc.7b03851 J. Agric. Food Chem. 2017, 65, 8523−8537