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Article

Synthesis, Herbicidal Activity, and Molecular Mode of Action Evaluation of Novel Quinazolinone—Phenoxypropionate Hybrids Containing a Diester Moiety

by
Shumin Wang
1,†,
Na Li
1,†,
Shibo Han
1,
Shuyue Fu
1,
Ke Chen
1,2,
Wenjing Cheng
3,* and
Kang Lei
1,*
1
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng 252059, China
2
Department of Biotechnology, The University of Suwon, Hwaseong 18323, Republic of Korea
3
Liaocheng Urban Garden Management and Service Center, Liaocheng 252059, China
*
Authors to whom correspondence should be addressed.
†
Authors contributed equally to this work.
Agronomy 2024, 14(9), 2124; https://doi.org/10.3390/agronomy14092124
Submission received: 31 July 2024 / Revised: 11 September 2024 / Accepted: 16 September 2024 / Published: 18 September 2024
(This article belongs to the Special Issue Herbicides Toxicology and Weeds Herbicide-Resistant Mechanism—Series II)
Browse Figures
Versions Notes

Abstract

:
To develop aryloxyphenoxypropionate herbicides with novel structure and improved activity, a total of twenty-eight novel quinazolinone–phenoxypropionate derivatives containing a diester moiety were designed and synthesized. The herbicidal bioassay results in the greenhouse showed that QPEP-I-4 exhibited excellent herbicidal activity against E. crusgalli, D. sanguinalis, S. alterniflora, E. indica, and P. alopecuroides with inhibition rates >80% at a dosage of 150 g ha−1 and displayed higher crop safety to G. hirsutum, G. max, and A. hypogaea than the commercial herbicide quizalofop-p-ethyl. Studying the herbicidal mechanism by phenotypic observation, membrane permeability evaluation, and transcriptomic analysis revealed that a growth inhibition of plants by QPPE-I-4 was the result from damage of the plants’ biomembrane. The evaluation of ACCase activity in vivo indicated that QPPE-I-4 could inhibit ACCase and may be a new type of ACCase inhibitor. The present work indicated that QPPE-I-4 could represent a lead compound for further developing novel AOPP herbicides.

1. Introduction

Weeds affect crop growth by competing for resources such as light, water, space, and nutrients, resulting in crop yield losses in agriculture. Herbicides are the most extensively used agrochemicals for controlling weeds and play a pivotal role in ensuring global food security [1]. Among the known herbicides, aryloxyphenoxypropionates (AOPPs) are a class of herbicides that can effectively control annual or perennial gramineous weeds in dicotyledonous crop fields. AOPP herbicides can inhibit acetyl-CoA carboxylase (ACCase), thus interfering with the synthesis of fatty acids, resulting in an increased permeability of the cell membrane of plants, plant metabolites leaking out, and finally, the death of the plants [2,3,4,5,6,7]. Owing to the advantages of AOPP herbicides such as low application rates, long-lasting effects, low toxicity and little residue, a large number of studies have been conducted on the screening of AOPP herbicides, and more than 20 commercial AOPP herbicides have been reached the market place. However, the repeated use of AOPP herbicides inevitably lead to the emergence of herbicide-resistant weeds [8,9,10,11,12,13,14,15,16]. Therefore, there is an urgent demand for the discovery of AOPP herbicides with novel structures and improved activity.
In our previous work [17,18], we designed and synthesized a series of quinazolinone–phenoxypropionate derivatives (QPP) through replacing the aryl moiety of AOPP herbicides with a quinazolin-4(3H)-one moiety (Figure 1). According to the data of herbicidal activity, we found that the substituent R1 and R2 on the quinazolin-4(3H)-one moiety displayed significant effects on herbicidal activity, and QPP-I was identified as a potential herbicidal lead compound. Therefore, as a continuation of the development of new AOPP herbicides with a novel structure and improved activity, we performed further modifications on the lead compound QPP-I.
On the one hand, AOPP herbicides are in the form of formulated ester, providing more lipophilicity and increased capacity to cross cellular membranes. Moreover, the substituent at the position of the ester moiety of AOPP herbicides has an important effect not only on activity but also on crop selectivity [19,20,21,22,23]. On the other hand, lipophilic carboxylates are the common structural fragments in pesticides (Figure 1B), and some studies have verified that the introduction of lipophilic carboxylate can improve biological activity [24,25,26,27,28]. These facts inspired our current hypothesis that the introduction of lipophilic carboxylates into an ester moiety of QPP-I may result in novel lead compounds with improved herbicidal activity. Therefore, in this work, a series of novel quinazolinone–phenoxypropionate derivatives containing a diester moiety (QPPE) were designed and synthesized based on the principle of substructure splicing (Figure 1C), and their herbicidal activities, structure–activity relationship (SAR) and molecular mode of action were evaluated to develop a novel AOPP herbicide.

2. Materials and Methods

2.1. General Information

All reagents and solvents, purchased form Energy Chemical (Pudong, Shanghai, China) or Tokyo Chemical Industry (Tokyo, Japan), were of analytical grade and used without further purification. Column chromatography purification was carried out using silica gel column chromatography (silica gel 200–300 mesh) (Qingdao Makall Group Co., Ltd., Qingdao, China). The melting points were determined on an X-4 binocular microscope melting point apparatus (Gongyi Tech. Instrument Co., Gongyi, China) and were uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded in CDCl3 as a solvent on a Bruker AV-500 spectrometer (Bruker Corp., Billerica, MA, USA) with tetramethylsilane (TMS) as the internal reference, and chemical shift values (δ) were given in parts per million (ppm). High-resolution mass spectra (HRMS) data were determined with a 6224 TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA) instrument. The crystal structure was determined on a Saturn 724 CCD area-detector diffractometer (Rigaku, Tokyo, Japan). A transmission electron microscopic (TEM) image was collected on a Hitachi-7800 TEM (Tokyo, Japan).

2.2. Synthesis Procedures of Target Compounds

The series target compounds QPPE-I to QPPE-IV were synthesized according to Scheme 1. The yields were not optimized.

2.2.1. General Procedure for Preparation of Intermediates 2a-2d

The intermediates 2a-2d were prepared following a reported method [29]. A representative example for the synthesis of 2a: 2-Amino-5-fluorobenzoic acid 1a (15.5 g, 100 mmol), methyl isothiocyanate (8.0 g, 110 mmol), Et3N (11.1 g, 110 mmol), and EtOH (250 mL) were sequentially added to a 500 mL three-neck flask. The reaction mixture was stirred for 3 h at 80 °C. After that, the reaction mixture cooled to 25 °C, the resulting precipitate was filtered, and the solid was washed with 100 mL EtOH and 100 mL hexane and dried under reduced pressure to obtain intermediate 2a as a white solid (18.8 g, yield: 89.5%).
The intermediates 2b-2d were prepared by a procedure similar to that for intermediate 2a. The data and spectra of 1H NMR of intermediates 2a-2d are given in the Supporting Information.

2.2.2. General Procedure for Preparation of Intermediates 3a-3d

The intermediates 3a-3d were prepared following a reported method [29]. A representative example for the synthesis of 3a: Sulfuryl chloride (SO2Cl2, 12.0 g, 89.5 mmol) was added to a 300 mL of CHCl3 solution of 2a (18.8 g, 89.5 mmol), and the solution was stirred for 2 h at 60 °C. After the reaction was complete (TLC monitoring), the solution was cooled to 25 °C and diluted with 300 mL CH2Cl2 (DCM). The solution was washed with saturated NaCl solution and dried with anhydrous Na2SO4 for 6 h. The solvent was removed under reduced pressure, and the crude product was purified via a chromatograph on silica gel using petroleum ether/ethyl acetate (v/v, 40:1) as an eluting agent to obtain the intermediate 3a as a white solid (9.1 g, yield: 47.9%).
The intermediates 3b-3d were prepared by a procedure similar to that for intermediate 3a. The data and spectra of 1H NMR of intermediates 3a-3d are given in the Supporting Information.

2.2.3. General Procedure for Preparation of Series Target Compounds QPPE-I to QPPE-IV

A representative example for the synthesis of QPPE-I-1: (R)-2-(4-Hydroxyphenoxy) propanoic acid (3.6 g, 20 mmol) was dissolved in 50 mL of DMF, and K2CO3 (5.5 g, 40 mmol) was then added in two batches. The reaction mixture was stirred for 1.0 h at 75 °C, and then intermediate 3a (4.2 g, 20 mmol) was added. The reaction mixture was stirred for 7.0 h at 75 °C. After the reaction was complete (TLC monitoring), 150 mL of ice water was poured into the reaction system, and the pH was adjusted to 4–5 by 1 M HCl followed by extraction with ethyl acetate (3 × 50 mL). The organic layer was washed with saturated NaCl solution and dried with anhydrous Na2SO4. The solvent was removed using a rotary flash evaporator, and the crude product 4a was used without further purification.
The crude product 4a (358 mg, 1 mmol) was dissolved in 10 mL of DCM in a 25 mL flask, and then oxalyl chloride (254 mg, 2 mmol) and DMF (one drop) was added. The mixture was stirred for 12 h at room temperature. After that, the solvent was removed by a rotary flash evaporator, and the crude product 5a was obtained. Subsequently, 5a was dissolved in 10 mL of DCM, and then ethyl glycolate (156 mg, 1.5 mmol), 4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol), and Et3N (202 mg, 2 mmol) were sequentially added to the solution, and the reaction mixture was stirred for 12 h at room temperature. After the reaction was complete (TLC monitoring), aqueous hydrochloric acid solution (1 M, 20 mL) was added to the reaction system. The organic layer was separated and washed with water and saturated NaCl solution, dried with anhydrous Na2SO4, and concentrated by a rotary flash evaporator. The residue was purified through a chromatograph on silica gel using petroleum ether/ethyl acetate (v/v, 20:1) as an eluting agent to give target compound QPPE-I-1 as a white solid (193 mg, yield: 43.5%).
The target compounds QPPE-I-2 to QPPE-I-7 and series target compounds QPPE-II to QPPE-IV were synthesized by a similar procedure to compound QPPE-I-1. The data and spectra of 1H NMR, 13C NMR, and HRMS of all target compounds are given in the Supporting Information.

2.3. X-ray Diffraction Analysis of the Target Compound QPPE-I-7

The target compound QPPE-I-7 was crystallized from a mixture of dichloromethane and methanol (v/v, 2:1) to give colorless crystals suitable for X-ray diffraction analysis. Crystallographic data of the target compound QPPE-I-7 had been deposited with the Cambridge Crystallographic Data Centre as supplementary publications, with the deposition number 2372256. The detail data can be acquired free of charge from http://www.ccdc.cam.ac.uk/ (accessed on 25 July 2024).

2.4. Evaluation of Herbicidal Activity

According to our previously reported methods [30,31,32], the post-emergence herbicidal activities of all target compounds against four representative plants (Brassica campestris, Amaranthus retroflexus, Echinochloa crusgalli, and Digitaria sanguinalis) were evaluated in the greenhouse. Furthermore, monocotyledon weeds E. crusgalli, D. sanguinalis, Pennisetum alopecuroides, Setaria viridis, Eleusine indica, Elymus dahuricus, and Spartina alterniflora were selected to screen the herbicidal spectrum of QPPE-I-4. Quizalofop-p-ethyl (QZ) was selected as a positive control. Briefly, 15 weed seeds were evenly sown in an 8 cm × 7 cm × 7 cm plastic pot with a 2:1 w/w sandy soil and nutrient matrix. Seedlings were grown in a greenhouse at the temperature 28 ± 2 °C with a 12 h:12 h light/dark photoperiod. The tested compounds were dissolved in 100% DMF and then diluted with Tween-80 (concentration: 100 g/L). The resulting solutions were diluted with water to the appropriate concentrations before use, and the content of DMF did not exceed 0.1%. When the two true leaves were expanded, the seedlings were thinned to 10 plants per plastic pot and sprayed with the tested compounds using a laboratory sprayer (machine model: 3WP-2000, Nanjing Research Institute for Agricultural Mechanization, Nanjing, National Ministry of Agriculture of China) equipped with a flat-fan nozzle delivering 280 L ha−1 at 230 kPa. The doses of the tested compounds were set at 150, 75, 37.5, 18.8, and 9.4 g ha−1. A mixture of the same amount of water, N, N-dimethylformamide, and Tween 80 was sprayed as the control. Each treatment was conducted in triplicate. After 21 days, the herbicidal activities of the tested compounds were evaluated. The inhibition rate was calculated by the following formula: inhibition rate (%) = ((fresh weight of control − fresh weight of treatment)/fresh weight of control) × 100%.

2.5. Safety for Crops

The compound displaying the most activity, QPPE-I-4, was selected for crop safety assay. Oryza sativa, Triticum aestivum, Zea mays, Panicum miliaceum, Gossypium hirsutum, Arachis hypogaea and Glycine max were selected as representative crops, and the assay methods were similar to those previously reported. The experiment was conducted when the crops reached the four-leaf stage. The tested compound QPPE-I-4 was applied at 150 g ha−1 with three replications per test. After 21 days, the crop damage of each compound was evaluated. The data represented the percent displaying damage compared to the control, where the complete injury of the target is 100 and no injury is 0.

2.6. Phenotypic Study of P. miliaceum

When P. miliaceum was grown to the 2-leaf stage, the macrophenotypic study of P. miliaceum was performed after seedling treated with QPPE-I-4 at 150 g ha−1 concentration for 7 day. Meanwhile, the leaf cell substructure of P. miliaceum seedlings was detected by TEM. The TEM samples were processed as described by Houot et al. [33]. Briefly, leaf samples of the control and QPPE-I-4-treated plantlets were cut to 1 cm2 pieces and fixed for over 12 h in a water solution containing 2.5% glutaraldehyde. After pouring out the fixative solution, samples were treated with 1.0% OsO4 for 1.5 h and dehydrated in acetone several times. Subsequently, samples were embedded in epoxy resin. The resin blocks were trimmed to 70–90 nm thickness using a Reichert Ultracuts ultramicrotome, which were stained with uranyl acetate, followed by lead citrate. After drying, the samples were observed with a Hitachi-7800 TEM.

2.7. Determination of Cell Membrane Permeability

According to a previous method [34], when P. miliaceum was grown to the 2-leaf stage, seedlings was treated with QPPE-I-4 and QZ at a dosage of 150 g ha−1, respectively. At 48, 96, 144, 192, and 240 h after the treatment, leaves of the plants were excised at a petiole. The excised leaves were soaked into 10 mL of distilled water in a beaker and shaken gently in a water bath at room temperature. After 3 h, the conductivity of the ambient solution was measured with an electric conductivity meter (DDS-307, INESA, Shanghai, China).

2.8. Transcriptome Study

When P. miliaceum was grown to the 2-leaf stage in the greenhouse, seedlings with consistent growth were selected to be treated with QPPE-I-4 at a dosage of 150 g ha−1. At 1 h after the treatment, 0.5 g of fresh P. miliaceum seedlings were excised and weighed into a 15 mL centrifuge tube, respectively, and quickly frozen and stored in a −80 °C refrigerator for RNA extraction. The treatment with water was selected as control. Three replicate samples were collected from control plants and QPPE-I-4-treated plants. Total RNA extraction and RNA-Seq analysis were performed by Beijing Biomarker Technologies Co., Ltd., Beijing, China. The resulting p values were adjusted using the Benjamini and Hochberg’s approach for controlling the false discovery rate. Genes with an adjusted fold change ≥ 2 and FDR < 0.01 found by DESeq2 were assigned as differentially expressed. A Gene Ontology (GO) enrichment analysis of the differentially expressed genes (DEGs) was implemented by the clusterProfiler packages based Wallenius non-central hyper-geometric distribution. KOBAS database and clusterProfiler software (1.20.0) was used to test the statistical enrichment of differential expression genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.

2.9. ACCase Inhibition Activity Assay

When P. miliaceum was grown to the 2-leaf stage, seedlings were sprayed with QPPE-I-4 using a laboratory sprayer. The dosage of QPPE-I-4 was set at 150 g ha−1, according to the preliminary experiment, with water used as the control. At 1, 3, 6, 12, 24, 48, and 96 h and 120 h after the treatment, 0.1 g of fresh P. miliaceum seedlings was excised and weighed into a 1.5 mL centrifuge tube for the ACCase enzyme inhibition assay. Three replicate samples were collected from control plants and QPPE-I-4-treated plants for each time point. The ACCase enzyme inhibition assay was performed by the method of the ACCase activity assay kit according to the manufacturer’s instructions (Solarbio Science & Technology Co., Ltd., Beijing, China). The absorbance [optical density (OD) value] was determined at 660 nm.

3. Results and Discussion

3.1. Chemistry

The series target compounds QPPE-I to QPPE-IV were prepared via a five-step synthetic route as depicted in Scheme 1. First, anthranilic acids 1a-1d reacted with methyl isothiocyanate in EtOH by using Et3N as a base to provide intermediates 2a-2d, which were reacted with SO2Cl2 in CHCl3 to provide intermediates 3a-3d. Then, the important intermediates 4a-4d were obtained by the nucleophilic substitution reaction between intermediates 3a-3d and (R)-2-(4-hydroxyphenoxy)propionic acid in DMF using K2CO3 as a base. Finally, intermediates 4a-4d reacted with oxalyl chloride in the presence of a catalytic amount of DMF to produce the corresponding acyl chlorides 5a-5d, which were reacted with an alcohol ester in the presence of Et3N and a catalytic amount of DMAP to afford the series target compounds QPPE-I to QPPE-IV in yields of 31.4–61.4%. The structures of all the target compounds were characterized via 1H NMR, 13C NMR, and HRMS. In addition, the structure of compound QPPE-I-7 was confirmed using X-ray diffraction analysis (CCDC 2372256; Figure 2).

3.2. Herbicidal Activities and SAR

The initial herbicidal activities of all the target compounds against dicotyledon weeds, including B. campestris and A. retroflexus, and monocotyledon weeds, including E. crusgalli and D. sanguinalis, were evaluated at a dosage of 150 g ha−1 under the post-emergence condition in the greenhouse. The commercial herbicide quizalofop-p-ethyl was selected as a positive control sample. As observed in Figure 3, most of the target compounds exhibited moderate to good total herbicidal activity against the tested weeds. Among them, compounds such as QPPE-I-3, QPPE-I-4, QPPE-I-6, QPPE-II-1, QPPE-II-3, and QPPE-II-4 exhibited promising herbicidal activity with a sum inhibition rate > 200%, which equaled that of quizalofop-p-ethyl (sum inhibition rate = 213%). A further analysis of the herbicidal data revealed that the series of compounds QPPE-I (R = 6-F) and QPPE-II (R = 6-Cl) possessed a higher sum inhibition rate than that of QPPE-III (R = 6-Me) and QPPE-IV (R = 7-F), and the herbicidal trend in these compounds was QPPE-I (R = 6-F) or QPPE-II (R = 6-Cl) > QPPE-III (R = 6-Me) > QPPE-IV (R = 7-F). These results demonstrated that the type and position of the R group on the benzene ring of the quinazolin-4(3H)-one moiety had a significant effect on herbicidal activity, and the introduction of weak withdrawing electron effect groups at the sixth position of the benzene ring of the quinazolin-4(3H)-one moiety was conducive to improving herbicidal activity. In addition, it was easy to observe that all of the target compounds distinctly exhibited stronger herbicidal activities against monocotyledonous plants E. crusgalli and D. sanguinalis than against dicotyledonous plants B. campestris and A. retroflexus, implying the target compounds could be developed as selective herbicides to control monocotyledon weeds.
To obtain a detailed SAR of the series compounds QPPE-I and QPPE-II, and to further explore their herbicidal activities against monocotyledonous plants, we performed a second round of herbicidal activity screening by using a dose reduction with serial two-fold dilutions method. As observed in Figure 4, the herbicidal activity of series compounds QPPE-I and QPPE-II became progressively lower with the dosage decreased from 75 to 9.4 g ha−1, and all of the tested compounds had lower herbicidal activity than that of quizalofop-p-ethyl. Delightfully, however, the most active target compound QPPE-I-4 still displayed moderate herbicidal activity against the two tested weeds, with a sum inhibition rate of 105% at a dosage of 9.4 g ha−1. This finding demonstrated that compound QPPE-I-4 could be selected as a potential lead compound for further study. Moreover, upon decreasing the dosage, the SAR of series compounds QPPE-I and QPPE-II becomes gradually obvious. At a lower dosage, the series compound QPPE-I (R = 6-F) displayed better sum herbicidal activity against the two tested weeds than that of the corresponding series compound QPPE-II (R = 6-Cl) on the whole, which may be attributed to the fact that the introduction of a fluorine atom into the target compounds could improve their stability and, in turn, could potentially be advantageous to herbicidal activity [35,36].
In addition, it was found that the substituent R1 also displayed a significant impact on herbicidal activity. For example, at a dosage of 9.4 g ha−1, the sum herbicidal inhibition rates of compounds QPPE-I-4 and QPPE-II-4 (R1 = 2-ethoxy-2-oxoethyl) were 3.5-fold and 12.5-fold higher than that of QPPE-I-7 and QPPE-II-7 (R1 = (1-ethoxycarbonyl)cyclopropylmethyl), respectively. According to the data of series compound QPPE-I at the dosage of 9.4 g ha−1, when the R1 group of the target compound was straight-chain carboxylates (i.e., QPPE-I-1 to QPPE-I-3), the sum inhibition rate was decreased with the extension of the carbon chain. Comparing the Clog p values of compounds QPPE-I-1, QPPE-I-2 and QPPE-I-3 revealed that compounds with a higher Clog p value possessed lower herbicidal activity, which may be caused by the poor uptake and translocation of the compound in plants due to relatively high lipophilicity [37]. When a branch-chain carboxylate was introduced into the ester moiety of QPPE-I, the sum herbicidal inhibition rates of QPPE-I-4 and QPPE-I-5 increased when compared with the corresponding compounds bearing straight-chain carboxylates (i.e., QPPE-I-2 and QPPE-I-3). Notably, although compounds QPPE-I-4 and QPPE-I-5 had relatively higher Clog P values than QPPE-I-1 and QPPE-I-2, they exhibited slightly higher sum inhibition rates than that of QPPE-I-1 and QPPE-I-2, respectively, implying that hydrophobicity was not the singular driver of the improvement in herbicidal activity, and the steric factors of the substituent R1 also played an significant impact on herbicidal activity. Collectively, the following order of the influence of the R1 group can be summarized: 1-ethoxy-1-oxopropan-2-yl > 2-ethoxy-2-oxoethyl > 1-ethoxy-1-oxobutan-3-yl > 3-ethoxy-3-oxopropyl > 4-ethoxy-4-oxobutyl > 2-(ethoxycarbonyl)allyl > (1-ethoxycarbonyl)cyclopropylmethyl. The effect of substituent R1 on the herbicidal activity of series compound QPPE-II was similar to that of series compound QPPE-I.

3.3. Herbicidal Spectrum and Crop Safety of Compound QPPE-I-4

Based on the results of the second round of screening, compound QPPE-I-4 was confirmed to have the highest herbicidal potency among all the target compounds. To investigate whether QPPE-I-4 could be developed as a potential herbicide or not, its herbicidal spectrum and crop safety were further evaluated at a rate of 150 g ha−1 under the post-emergence condition. The herbicidal spectrum results showed that QPPE-I-4 displayed an excellent control effect on E. crusgalli, D. sanguinalis, S. alterniflora, E. indica, and P. alopecuroides, with an inhibition rate of >80%, which was comparable to quizalofop-p-ethyl (Figure 5). In addition, the crop safety test showed that, after the seven kinds of crops were treated with QPPE-I-4, G. hirsutum, G. max, and A. hypogaea exhibited complete tolerance toward QPPE-I-4, while the injury rates of QPPE-I-4 to O. sativa, Z. mays and T. aestivum were 74%, 79%, and 81%, respectively (Table 1). Taken together, the target compound QPPE-I-4 could be developed as a post-emergence herbicide for monocotyledonous weed control in G. hirsutum, G. max and A. hypogaea fields.

3.4. Molecular Mode of Action of the Compound QPPE-I-4

The molecular mode of action of the most activity compound QPPE-I-4 was explored with P. miliaceum as a model plant. As shown in Figure 6A–C, phytotoxicity was evidently observed in P. miliaceum leaves, with symptoms of leaf curl/distortion, partial chlorosis, and damage to growing points for the QPPE-I-4 treatment at 7 d, which was very similar to the commercial AOPP herbicide quizalofop-p-ethyl. TEM images revealed that, when compared with the control (Figure 6D,E), the chloroplast membrane structure of P. miliaceum leaves was damaged and the chloroplast disintegrated after treatment with QPPE-I-4, thereby resulting in decreased chloroplast levels in P. miliaceum leaf cells (Figure 6G,H). Furthermore, it was easily observed that treatment with QPPE-I-4 resulted in plasmolysis (Figure 6H). Subsequently, we further investigated the effect of QPPE-I-4 on leaf cell membrane permeability. It was found that a significant electrolyte leakage of the leaf cell began at 144 h after being treated with QPPE-I-4, and electrolyte leakage reached a stable state at 192 h, which was similar to quizalofop-p-ethyl (Figure 7). Collectively, these results could explain the reason for symptoms of the leaf becoming partially yellow, withering, and necrosis, demonstrating that compound QPPE-I-4 caused damage to the membrane system of the plant.
To further understand the molecular mode of action, the RNA sequencing was then performed to identify the differential expression genes (DEGs) of P. miliaceum after being treated with compound QPPE-I-4 for 1 h. As shown in Figure 8A,B, in total, 150 DEGs with a fold change ≥ 2 and FDR < 0.01 were identified, and there were 88 up-regulated DEGs and 65 down-regulated DEGs. To understand the functions of these 150 DEGs, GO annotation and KEGG annotation were performed. As observed in Figure 9A, the KEGG annotation showed that the significantly enriched metabolic pathway was related to phenylalanine biosynthesis. As reported [38], phenylalanine is a critical metabolic node that plays an essential role in the interconnection between the primary and secondary metabolism of plants, and it is a precursor of numerous compounds that are crucial for defense against different types of stresses. Thus, it was speculated that P. miliaceum produced a stress response to QPPE-I-4-induced stress at 1 h. Meanwhile, GO annotation was performed and analyzed on the 150 DEGs, being classified into the molecular function, cell component, and biological process (Figure 9B–D). The significantly enriched GO terms related to cellular components were thylakoid membrane, plastid thylakoid, obsolete thylakoid part, photosynthetic membrane, and plastid thylakoid membrane. The significantly enriched GO terms related to biological process were the regulation of the tetrapyrrole metabolic process, obsolete regulation of the cofacor metabolic process and regulation of the chlorophyll metabolic process. The significantly enriched GO term related to molecular function was phenylalanine ammonia-lyase activity. These analysis results demonstrated that a growth inhibition of P. miliaceum by QPPE-I-4 was the result of the disruption of the plants’ biomembranes, which was confirmed by the above results of the phenotypic study.
Since compound QPPE-I-4 had similar motif and phytotoxic phenotypes to AOPP herbicides, it was speculated that QPPE compounds had a similar herbicidal mechanism to AOPP herbicides. Thus, the in vivo inhibition of the ACCase activity assay of QPPE-I-4 was performed. As shown in Figure 10, QPPE-I-4 exhibited in vivo inhibition against ACCase activity, with inhibition rates of 10%, 16%, 26%, 47%, and 62% at 1 h, 48 h, 72 h, 96 h, and 120 h, respectively, which were comparable to those of the commercial AOPP herbicide quizalofop-p-ethyl. Interestingly, the inhibition rate of enzyme activity changed over time and showed a trend of first decreasing and then increasing, which may have been caused by plants’ stress response to QPPE-I-4. These results indicate that QPPE-I-4 can inhibit in vivo ACCase activity in plants and may be an ACCase inhibitor.

4. Conclusions

In summary, a total of twenty-eight novel quinazolinone−phenoxypropionate derivatives containing a diester moiety were prepared in moderate yield and tested for herbicidal activity. The results of herbicidal activity revealed that the type and position of the R group on the benzene ring of the quinazolin-4(3H)-one moiety displayed an important effect on herbicidal activity, and the type of R1 group also had effect on herbicidal activity. The (R = 6-F, R1 = 1-ethoxy-1-oxopropan-2-yl) pattern was the optimal orientation, and QPPE-I-4 was confirmed as a potential herbicide lead compound due to its good herbicidal activity, moderate herbicidal spectrum and good crop safety. Furthermore, the study of the molecular mode of action of QPPE-I-4 by phenotypic observation, membrane permeability evaluation, transcriptomic analysis and in vivo ACCase activity evaluation suggested that QPPE-I-4 might be a novel ACCase inhibitor, which induced damage to the membrane system of the plants. The present work indicated that QPPE-I-4 could represent a lead compound for further developing novel AOPP herbicides. Further study on the structural optimization of QPPE-I-4 is ongoing in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/agronomy14092124/s1, Figure S1 1H NMR spectrum of QPPE-I-1, CDCl3, 500 MHz. Figure S2 13C NMR spectrum of QPPE-I-1, CDCl3, 125 MHz. Figure S3 HRMS spectrum of QPPE-I-1. Figure S4 1H NMR spectrum of QPPE-I-2, CDCl3, 500 MHz. Figure S5 13C NMR spectrum of QPPE-I-2, CDCl3, 125 MHz. Figure S6 HRMS spectrum of QPPE-I-2. Figure S7 1H NMR spectrum of QPPE-I-3, CDCl3, 500 MHz. Figure S8 13C NMR spectrum of QPPE-I-3, CDCl3, 125 MHz. Figure S9 HRMS spectrum of QPPE-I-3. Figure S10 1H NMR spectrum of QPPE-I-4, CDCl3, 500 MHz. Figure S11 13C NMR spectrum of QPPE-I-4, CDCl3, 125 MHz. Figure S12 HRMS spectrum of QPPE-I-4. Figure S13 1H NMR spectrum of QPPE-I-5, CDCl3, 500 MHz. Figure S14 13C NMR spectrum of QPPE-I-5, CDCl3, 125 MHz. Figure S15 HRMS spectrum of QPPE-I-5. Figure S16 1H NMR spectrum of QPPE-I-6, CDCl3, 500 MHz. Figure S17 13C NMR spectrum of QPPE-I-6, CDCl3, 125 MHz. Figure S18 HRMS spectrum of QPPE-I-6. Figure S19 1H NMR spectrum of QPPE-I-7, CDCl3, 500 MHz. Figure S20 13C NMR spectrum of QPPE-I-7, CDCl3, 125 MHz. Figure S21 HRMS spectrum of QPPE-I-7. Figure S22 1H NMR spectrum of QPPE-Ⅱ-1, CDCl3, 500 MHz. Figure S23 13C NMR spectrum of QPPE-Ⅱ-1, CDCl3, 125 MHz. Figure S24 HRMS spectrum of QPPE-Ⅱ-1. Figure S25 1H NMR spectrum of QPPE-Ⅱ-2, CDCl3, 500 MHz. Figure S26 13C NMR spectrum of QPPE-Ⅱ-2, CDCl3, 125 MHz. Figure S27 HRMS spectrum of QPPE-Ⅱ-2. Figure S28 1H NMR spectrum of QPPE-Ⅱ-3, CDCl3, 500 MHz. Figure S29 13C NMR spectrum of QPPE-Ⅱ-3, CDCl3, 125 MHz. Figure S30 HRMS spectrum of QPPE-Ⅱ-3. Figure S31 1H NMR spectrum of QPPE-Ⅱ-4, CDCl3, 500 MHz. Figure S32 13C NMR spectrum of QPPE-Ⅱ-4, CDCl3, 125 MHz. Figure S33 HRMS spectrum of QPPE-Ⅱ-4. Figure S34 1H NMR spectrum of QPPE-Ⅱ-5, CDCl3, 500 MHz. Figure S35 13C NMR spectrum of QPPE-Ⅱ-5, CDCl3, 125 MHz. Figure S36 HRMS spectrum of QPPE-Ⅱ-5. Figure S37 1H NMR spectrum of QPPE-Ⅱ-6, CDCl3, 500 MHz. Figure S38 13C NMR spectrum of QPPE-Ⅱ-6, CDCl3, 125 MHz. Figure S39 HRMS spectrum of QPPE-Ⅱ-6. Figure S40 1H NMR spectrum of QPPE-Ⅱ-7, CDCl3, 500 MHz. Figure S41 13C NMR spectrum of QPPE-Ⅱ-7, CDCl3, 125 MHz. Figure S42 HRMS spectrum of QPPE-Ⅱ-7. Figure S43 1H NMR spectrum of QPPE-Ⅲ-1, CDCl3, 500 MHz. Figure S44 13C NMR spectrum of QPPE-Ⅲ-1, CDCl3, 125 MHz. Figure S45 HRMS spectrum of QPPE-Ⅲ-1. Figure S46 1H NMR spectrum of QPPE-Ⅲ-2, CDCl3, 500 MHz. Figure S47 13C NMR spectrum of QPPE-Ⅲ-2, CDCl3, 125 MHz. Figure S48 HRMS spectrum of QPPE-Ⅲ-2. Figure S49 1H NMR spectrum of QPPE-Ⅲ-3, CDCl3, 500 MHz. Figure S50 13C NMR spectrum of QPPE-Ⅲ-3, CDCl3, 125 MHz. Figure S51 HRMS spectrum of QPPE-Ⅲ-3. Figure S52 1H NMR spectrum of QPPE-Ⅲ-4, CDCl3, 500 MHz. Figure S53 13C NMR spectrum of QPPE-Ⅲ-4, CDCl3, 125 MHz. Figure S54 HRMS spectrum of QPPE-Ⅲ-4. Figure S55 1H NMR spectrum of QPPE-Ⅲ-5, CDCl3, 500 MHz. Figure S56 13C NMR spectrum of QPPE-Ⅲ-5, CDCl3, 125 MHz. Figure S57 HRMS spectrum of QPPE-Ⅲ-5. Figure S58 1H NMR spectrum of QPPE-Ⅲ-6, CDCl3, 500 MHz. Figure S59 13C NMR spectrum of QPPE-Ⅲ-6, CDCl3, 125 MHz. Figure S60 HRMS spectrum of QPPE-Ⅲ-6. Figure S61 1H NMR spectrum of QPPE-Ⅲ-7, CDCl3, 500 MHz. Figure S62 13C NMR spectrum of QPPE-Ⅲ-7, CDCl3, 125 MHz. Figure S63 HRMS spectrum of QPPE-Ⅲ-7. Figure S64 1H NMR spectrum of QPPE-Ⅳ-1, CDCl3, 500 MHz. Figure S65 13C NMR spectrum of QPPE-Ⅳ-1, CDCl3, 125 MHz. Figure S66 HRMS spectrum of QPPE-Ⅳ-1. Figure S67 1H NMR spectrum of QPPE-Ⅳ-2, CDCl3, 500 MHz. Figure S68 13C NMR spectrum of QPPE-Ⅳ-2, CDCl3, 125 MHz. Figure S69 HRMS spectrum of QPPE-Ⅳ-2. Figure S70 1H NMR spectrum of QPPE-Ⅳ-3, CDCl3, 500 MHz. Figure S71 13C NMR spectrum of QPPE-Ⅳ-3, CDCl3, 125 MHz. Figure S72 HRMS spectrum of QPPE-Ⅳ-3. Figure S73 1H NMR spectrum of QPPE-Ⅳ-4, CDCl3, 500 MHz. Figure S74 13C NMR spectrum of QPPE-Ⅳ-4, CDCl3, 125 MHz. Figure S75 HRMS spectrum of QPPE-Ⅳ-4. Figure S76 1H NMR spectrum of QPPE-Ⅳ-5, CDCl3, 500 MHz. Figure S77 13C NMR spectrum of QPPE-Ⅳ-5, CDCl3, 125 MHz. Figure S78 HRMS spectrum of QPPE-Ⅳ-5. Figure S79 1H NMR spectrum of QPPE-Ⅳ-6, CDCl3, 500 MHz. Figure S80 13C NMR spectrum of QPPE-Ⅳ-6, CDCl3, 125 MHz. Figure S81 HRMS spectrum of QPPE-Ⅳ-6. Figure S82 1H NMR spectrum of QPPE-Ⅳ-7, CDCl3, 500 MHz. Figure S83 13C NMR spectrum of QPPE-Ⅳ-7, CDCl3, 125 MHz. Figure S84 HRMS spectrum of QPPE-Ⅳ-7.

Author Contributions

Conceptualization, K.L.; methodology, K.L. and W.C.; validation, S.W. and N.L.; formal analysis, S.W. and N.L.; investigation, S.W. and N.L.; data curation, S.H., S.F. and K.C.; writing—original draft preparation, W.C.; writing—review and editing, K.L. and K.C.; project administration, K.L.; funding acquisition, K.L. All authors have read and agreed to the published version of the manuscript.

Funding

This project was financially supported by the National Natural Science Foundation of China (No. 31701827); the Natural Science Foundation of Shandong Province (No. ZR2023MC095); and the China Postdoctoral Science Foundation (No. 2020M671984).

Data Availability Statement

The data are contained within the article; further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Design of target compound QPPE by substructure splicing strategy. (A) Commercial AOPP herbicides; (B) Commercial herbicides containing a diester moiety; (C) The structure of designed target compound QPPE.
Figure 1. Design of target compound QPPE by substructure splicing strategy. (A) Commercial AOPP herbicides; (B) Commercial herbicides containing a diester moiety; (C) The structure of designed target compound QPPE.
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Scheme 1. General synthetic route for the series target compounds QPPE-I to QPPE-IV.
Scheme 1. General synthetic route for the series target compounds QPPE-I to QPPE-IV.
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Figure 2. X-ray crystal structure of the target compound QPPE-I-7.
Figure 2. X-ray crystal structure of the target compound QPPE-I-7.
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Figure 3. Effects (% inhibition) of the target compounds on the loss of plant weight at a dosage of 150 g ha−1 under the post-emergence condition; BC: B. campestris; AR: A. retroflexus; EC: E. crusgalli; DS: D. sanguinalis.
Figure 3. Effects (% inhibition) of the target compounds on the loss of plant weight at a dosage of 150 g ha−1 under the post-emergence condition; BC: B. campestris; AR: A. retroflexus; EC: E. crusgalli; DS: D. sanguinalis.
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Figure 4. Effects (% inhibition) of the target compounds on the loss of plant weight at different dosages in greenhouse testing; (A) at a dosage of 75 g ha−1; (B) at a dosage of 37.5 g ha−1; (C) at a dosage of 18.8 g ha−1; and (D) at a dosage of 9.4 g ha−1; EC: E. crusgalli; DS: D. sanguinalis.
Figure 4. Effects (% inhibition) of the target compounds on the loss of plant weight at different dosages in greenhouse testing; (A) at a dosage of 75 g ha−1; (B) at a dosage of 37.5 g ha−1; (C) at a dosage of 18.8 g ha−1; and (D) at a dosage of 9.4 g ha−1; EC: E. crusgalli; DS: D. sanguinalis.
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Figure 5. Herbicidal spectrum of compound QPPE-I-4 under post-emergence conditions at the dosage of 150 g ha−1. Abbreviation: EC, E. crusgalli; DS, D. sanguinalis; SA, S. alterniflora; ED, E. dahuricus; EI, E. indica; PA, P. alopecuroides; SV, S. viridis.
Figure 5. Herbicidal spectrum of compound QPPE-I-4 under post-emergence conditions at the dosage of 150 g ha−1. Abbreviation: EC, E. crusgalli; DS, D. sanguinalis; SA, S. alterniflora; ED, E. dahuricus; EI, E. indica; PA, P. alopecuroides; SV, S. viridis.
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Figure 6. Phenotype of P. miliaceum seedlings ((A), control; (B), treated with QPPE-I-4; (C), treated with QZ) and TEM images of P. miliaceum leaf cells (control: (D–F); treated with QPPE-I-4: (G–I)).
Figure 6. Phenotype of P. miliaceum seedlings ((A), control; (B), treated with QPPE-I-4; (C), treated with QZ) and TEM images of P. miliaceum leaf cells (control: (D–F); treated with QPPE-I-4: (G–I)).
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Figure 7. Effect of QPPE-I-4 and QZ on leaf cell permeability determined by changes in conductance of the ambient solution.
Figure 7. Effect of QPPE-I-4 and QZ on leaf cell permeability determined by changes in conductance of the ambient solution.
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Figure 8. Bar chart (A) and volcano plot (B) of gene expression in P. miliaceum leaves after being treated with QPPE-I-4 for 1 h.
Figure 8. Bar chart (A) and volcano plot (B) of gene expression in P. miliaceum leaves after being treated with QPPE-I-4 for 1 h.
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Figure 9. RNA sequencing analysis of P. miliaceum treated by QPPE-I-4. (A) KEGG analysis of differential expression genes; GO analysis of differential expression genes: (B) cell component; (C) molecular function; (D) biological process.
Figure 9. RNA sequencing analysis of P. miliaceum treated by QPPE-I-4. (A) KEGG analysis of differential expression genes; GO analysis of differential expression genes: (B) cell component; (C) molecular function; (D) biological process.
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Figure 10. In vivo inhibition of ACCase activity by QPPE-I-4 and QZ at different treatment time at a dosage of 150 g ha−1; Vertical bars represent mean ± SD; Some error bars of mean ± SD are obscured by data symbols.
Figure 10. In vivo inhibition of ACCase activity by QPPE-I-4 and QZ at different treatment time at a dosage of 150 g ha−1; Vertical bars represent mean ± SD; Some error bars of mean ± SD are obscured by data symbols.
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Table 1. Crop safety of compounds QPPE-I-4 and QZ at the dosage of 150 g ha−1 (injury rate) a.
Table 1. Crop safety of compounds QPPE-I-4 and QZ at the dosage of 150 g ha−1 (injury rate) a.
Comp.% Injury
O. sativaZ. maysT. aestivumP. miliaceumG. hirsutumG. maxA. hypogaea
QPPE-I-474 ± 379 ± 581 ± 392 ± 4000
QZ10088 ± 291 ± 410019 ± 314 ± 417 ± 3
a Each value represents the mean ± SD of three experiments.
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Wang, S.; Li, N.; Han, S.; Fu, S.; Chen, K.; Cheng, W.; Lei, K. Synthesis, Herbicidal Activity, and Molecular Mode of Action Evaluation of Novel Quinazolinone—Phenoxypropionate Hybrids Containing a Diester Moiety. Agronomy 2024, 14, 2124. https://doi.org/10.3390/agronomy14092124

AMA Style

Wang S, Li N, Han S, Fu S, Chen K, Cheng W, Lei K. Synthesis, Herbicidal Activity, and Molecular Mode of Action Evaluation of Novel Quinazolinone—Phenoxypropionate Hybrids Containing a Diester Moiety. Agronomy. 2024; 14(9):2124. https://doi.org/10.3390/agronomy14092124

Chicago/Turabian Style

Wang, Shumin, Na Li, Shibo Han, Shuyue Fu, Ke Chen, Wenjing Cheng, and Kang Lei. 2024. "Synthesis, Herbicidal Activity, and Molecular Mode of Action Evaluation of Novel Quinazolinone—Phenoxypropionate Hybrids Containing a Diester Moiety" Agronomy 14, no. 9: 2124. https://doi.org/10.3390/agronomy14092124

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