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Article

Design, Synthesis, and Herbicidal Activity of Novel 5-Acylbarbituric Acid Derivatives Containing a Pyrimidinedione Moiety

by
Ke Chen
1,
Shumin Wang
2,
Shuyue Fu
2,
Wei Gao
2,
Junehyun Kim
1,
Phumbum Park
1,
Rui Liu
1,* and
Kang Lei
2,*
1
Department of Biotechnology, The University of Suwon, Hwaseong City 18323, Gyeonggi-do, Republic of Korea
2
School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
*
Authors to whom correspondence should be addressed.
Agronomy 2025, 15(4), 777; https://doi.org/10.3390/agronomy15040777
Submission received: 16 February 2025 / Revised: 18 March 2025 / Accepted: 21 March 2025 / Published: 22 March 2025
(This article belongs to the Topic Research on Natural Bioactive Product-Based Pesticidal Agents—2nd Edition)
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Abstract

:
In continuation of our efforts to identify novel herbicide lead compounds with enhanced activity, a series of eighteen 5-acylbarbituric acid derivatives containing a pyrimidinedione moiety were designed and synthesized. Their herbicidal activities were subsequently evaluated in the greenhouse. Bioassay results demonstrated that most of the newly synthesized compounds exhibited significant herbicidal efficacy at a dosage of 150 g ha−1, with compounds BA-I-2, BA-II-2, BA-III-2, and BA-III-5 achieving complete inhibition of the tested weeds. Further investigation into the herbicidal spectrum revealed that compounds BA-II-2 and BA-III-2 displayed excellent herbicidal activity against 14 and 13 out of 16 tested weed species, respectively, with inhibition rates exceeding 80% at dosages as low as 18.8 g ha−1. More promisingly, compound BA-III-2 was found to be safe for Triticum aestivum at a dosage of 37.5 g ha−1. Molecular mode of action studies, including phenotypic observations, membrane permeability evaluations, and molecular docking, suggested that BA-III-2 may function as a protoporphyrinogen IX oxidase (PPO) inhibitor. The present work indicates that BA-III-2 holds potential as a PPO-inhibiting herbicide for effective weed control in wheat fields and is expected to provide important theoretical foundations for the development of novel and highly efficient herbicides.

1. Introduction

Weeds compete with crops for essential resources, including light, water, space, and nutrients, leading to significant reductions in crop yields and causing annual global losses exceeding $100 billion [1]. Herbicides are the most extensively used agrochemicals for reducing the harm caused by weeds and play a pivotal role in ensuring global food security. However, the widespread and irrational use of herbicides has caused some side effects, such as serious environmental problems and the emergence of herbicide-resistant weeds [2,3]. Consequently, there is a continuing need for the discovery of herbicides with an environmentally benign character, novel structures, and enhanced activity. The pivotal step in the development of novel herbicides is the identification of lead compounds. To date, natural products have served as lead compounds or sources of inspiration for the discovery of numerous contemporary herbicides [4,5,6]. These herbicides are distinguished by their unique modes of action, facile degradation, and excellent environmental compatibility. Furthermore, a substantial number of prior studies have demonstrated that the introduction of natural motifs constitutes an efficient approach for agrochemical discovery. Notable examples include synthetic herbicides, such as sulcotrione and glyphosate [7,8].
Pyrimidinedione is a significant chemical motif and structural unit present in various natural alkaloids and bioactive molecules (Figure 1) [9,10,11,12]. Numerous studies have demonstrated that compounds containing a pyrimidinedione moiety exhibit a broad spectrum of pharmacological properties, including antibacterial [13,14], antiviral [15,16,17,18], anticancer [19,20,21], immunomodulatory [22], and antihyperglycemic activities [23,24,25]. Additionally, compounds containing the pyrimidinedione moiety have been found to possess agrochemical properties, such as herbicidal activities [26,27,28,29,30,31]. The intriguing structural and biological characteristics of pyrimidinedione make it an attractive candidate for the development of novel herbicides. On the other hand, substructure splicing is a prominent strategy for identifying new lead compounds with herbicidal activity. Several examples of successful substructure splicing have been reported, including the design of the commercial herbicide quinotrione by combining fragments from mesotrione and natural quinoline products [32]. In our previous work [33], we designed and synthesized a series of 5-acylbarbituric acid derivatives as herbicides using the substructure splicing strategy and identified compound I as a promising lead compound (Figure 1). To further advance the development of herbicides with novel structures and enhanced activity, we propose to modify lead compound I by integrating the pyrimidinedione moiety into its benzene ring to construct novel 5-acylbarbituric acid derivatives (BA). This approach aims to facilitate the discovery of new herbicidal lead compounds with promising activity.
Based on the above facts, a series of BA derivatives were designed and synthesized, and their herbicidal activities, structure-activity relationships, and molecular mechanisms were systematically investigated. Notably, the compound BA identified in this study exhibits superior herbicidal activity compared to the lead compound I. To the best of our knowledge, this represents the first report on the herbicidal activity of 5-acylbarbiturate derivatives incorporating pyrimidinedione fragments.

2. Materials and Methods

2.1. Chemical Synthesis Procedures

The general synthesis route for the series target compounds BA-I~BA-III is shown in Scheme 1, and the structures of the series target compounds BA-I~BA-III are shown in Figure 2. Representative procedures for the synthesis of intermediates and target compounds are given below, and the yields were not optimized. The calculated oil/water partition coefficients (Clog P) were predicted using ChemBioDraw 12.0.

2.1.1. General Method for the Synthesis of Intermediates 3-I-(a-f) to 3-III-(a-f)

The intermediates 3-I-(a-f) to 3-III-(a-f) were synthesized according to a previously reported method [34]. A representative procedure for the preparation of intermediate 3-I-a is as follows: 3-nitrophenol (1a, 13.9 g, 100 mmol) and potassium carbonate (K2CO3, 7.6 g, 200 mmol) were dissolved in N,N-dimethylformamide (DMF, 200 mL), followed by the addition of ethyl bromoacetate (2a, 20.0 g, 120 mmol). The reaction mixture was stirred at an ambient temperature for 12 h. Upon completion of the reaction (monitored by thin-layer chromatography, TLC), 400 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (EtOAc, 3 × 200 mL). The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether/EtOAc (v/v, 50:1) as the eluent, yielding intermediate 3-I-a as a white solid (13.4 g, 59.6%). Intermediates 3-I-(b-f) to 3-III-(a-f) were prepared following a similar procedure.

2.1.2. General Method for the Synthesis of Intermediates 4-I-(a-f) to 4-III-(a-f)

The intermediates 4-I-(a-f) to 4-III-(a-f) were synthesized according to a previously reported method [35]. A representative procedure for the preparation of intermediate 4-I-a is as follows: Compound 3-I-a (7.6 g, 33.8 mmol) was dissolved in 200 mL of glacial acetic acid (AcOH), and iron powder (Fe, 18.9 g, 338 mmol) was added in three portions at room temperature. The mixture was vigorously stirred at room temperature for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was quenched by pouring 500 mL of ice water. The pH was adjusted to 7 using saturated sodium bicarbonate solution, followed by extraction with EtOAc (3 × 250 mL). The combined organic layers were washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (v/v, 5:1) as the eluent, yielding intermediate 4-I-a as a light-yellow oil (6.0 g, 91.0%). Intermediates 4-I-(b-f) to 4-III-(a-f) were prepared following a similar procedure.

2.1.3. General Method for the Synthesis of Intermediate 7

Intermediate 7 was synthesized according to a previously reported method [36] with slight modifications. Specifically, 60% sodium hydride (NaH, 6 g, 150 mmol) was dissolved in 250 mL of DMF. Ethyl (Z)-3-amino-4,4,4-trifluorobut-2-enoate 5 (18.3 g, 100 mmol) was subsequently added to the solution, and the mixture was stirred at room temperature for 30 min. Dimethylcarbamic chloride 6 (12.0 g, 110 mmol) was then introduced, and the reaction mixture was allowed to stir at room temperature for an additional 12 h. Upon completion of the reaction (monitored by TLC), the reaction solution was carefully poured into 500 mL of ice water and extracted three times with EtOAc (3 × 150 mL). The combined organic layers were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator, and the resulting residue was purified via silica gel column chromatography, eluting with a petroleum ether/EtOAc mixture (v/v, 20:1). Intermediate 7 was obtained as a light-yellow oil (15.6 g, yield: 61.4%).

2.1.4. General Method for the Synthesis of Intermediates 9-I-(a-f) to 9-III-(a-f)

The intermediates 9-I-(a-f) to 9-III-(a-f) were synthesized according to a previously reported method with minor modifications [37]. A representative example for the synthesis of 9-I-a is as follows: Compound 4-I-a (3.9 g, 20 mmol) was dissolved in AcOH (50 mL), and intermediate 7 (5.6 g, 22 mmol) was subsequently added. The reaction mixture was heated at 120 °C for 6 h under stirring. Upon completion of the reaction (monitored by TLC), the reaction mixture was quenched by pouring it into 200 mL of water, and the pH was adjusted to 7 using a saturated sodium bicarbonate (NaHCO3) solution. The aqueous phase was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed sequentially with saturated NaHCO3 solution, water, and saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford intermediate 8-I-a. This intermediate was then dissolved in DMF (50 mL), and K2CO3 (5.5 g, 40 mmol) and CH3I (3.1 g, 22 mmol) were added at room temperature. The reaction mixture was heated to 50 °C for 12 h while stirring. After completion of the reaction (monitored by TLC), the reaction mixture was poured into 100 mL of ice water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (v/v, 5:1) as the eluent to yield intermediate 9-I-a as a light-yellow liquid (3.6 g, 48.4%). Intermediates 8-I-(b-f) to 8-III-(a-f) and 9-I-(b-f) to 9-III-(a-f) were prepared following a similar procedure.

2.1.5. General Method for the Synthesis of Intermediates 10-I-(a-f) to 10-III-(a-f)

Representative example for the synthesis of 10-I-a: intermediate 9-I-a (1.9 g, 5.1 mmol) was dissolved in 40 mL of AcOH, followed by the addition of 1 mL of 98% sulfuric acid and 1 mL of water. The mixture was refluxed at 120 °C for 2 h and then cooled to room temperature. The mixture was poured into 80 mL of ice water and extracted with EtOAc (3 × 40 mL). The extracted organic layer was combined, washed with saturated sodium chloride solution, and dried with sodium sulfate. The solvent was removed under reduced pressure, resulting in the intermediate 10-I-a as a white solid (1.0 g, yield: 57.1%), which was used for the next step without further purification. The intermediates 10-I-(b-f) to 10-III-(a-f) were prepared by a procedure similar to that of 10-I-a.

2.1.6. General Method for the Synthesis of Target Compounds BA-I-(1-6) to BA-III-(1-6)

The target compounds BA-I-(1-6) to BA-III-(1-6) were synthesized according to a previously reported method with minor modifications [37]. A representative example for the synthesis of BA-I-1 is described as follows: Compound 10-I-a (1.0 g, 2.9 mmol) was dissolved in dichloromethane (DCM, 20 mL), and thionyl chloride (SOCl2, 20 mL) along with one drop of DMF was subsequently added. The reaction mixture was stirred at 60 °C for 12 h under an inert atmosphere. Subsequently, the solvent was removed under reduced pressure to afford acid chloride 11-I-a. This intermediate was then dissolved in 30 mL of DCM, followed by the addition of 1,3-dimethylbarbituric acid (452 mg, 2.9 mmol), 4-dimethylaminopyridine (DMAP, 48 mg, 0.4 mmol), and triethylamine (Et3N, 2.9 g, 29 mmol). The resulting mixture was stirred at room temperature for 72 h. Upon completion of the reaction (monitored by TLC), a 1 M hydrochloric acid solution (30 mL) was added to the reaction mixture, and the organic layer was separated. The organic phase was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography using a petroleum ether/EtOAc (v/v, 5:1) eluent system, yielding the target compound BA-I-1 as a white solid (703 mg, yield: 50.3%). Intermediates 11-I-(b-f) to 11-III-(a-f) were prepared by a procedure similar to that for 11-I-a, and target compounds BA-I-(2-6) to BA-III-(1-6) were prepared by a procedure similar to that for BA-I-1. The data of 1H NMR, 13C NMR, and HRMS of all target compounds are given in the Supporting Information.

2.2. Evaluation of Herbicidal Activity

According to the methods previously reported [37], the post-emergent herbicidal activities of series target compounds BA-I~BA-III against four representative plants (i.e., Brassica campestris, Amaranthus tricolor, Echinochloa crus-galli, and Digitaria sanguinalis) were evaluated in the greenhouse. Furthermore, sixteen weeds, i.e., B. campestris, A. tricolor, Lactuca indica, Portulaca oleracea, Taraxacum mongolicum, Chenopodium album, Bidens tripartita, Ipomoea nil, E. crus-galli, D. sanguinalis, Setaria viridis, Eleusine indica, Spartina alterniflora, Pennisetum alopecuroides, Chloris virgata, and Elymus dahuricus, commonly found in farmland in Shandong Province, China, were chosen to test the herbicidal spectrum of target compounds BA-II-2 and BA-III-2. Saflufenacil (SF) was selected as the positive control. Briefly, 15 to 20 weed seeds were uniformly sown in an 8-cm × 7-cm × 7-cm plastic pot filled with a 2:1 w/w mixture of sandy soil and nutrient matrix. The seedlings were cultivated in a greenhouse maintained at 28 ± 2 °C under a 16 h light: 8 h 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 distilled water (pH = 7) to the appropriate concentrations before use. 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 all target compounds were settled at 150 g ha−1 for the initial herbicidal screening. In the subsequent herbicidal screening, the dosages of the selected target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) were set at 75, 37.5, 18.8, and 9.4 g ha−1, respectively. Each treatment was replicated three times with a one-day interval between each repetition. A mixture of distilled water, DMF, and Tween 80 in equal proportions was sprayed as the control group. After a 14-day period, the herbicidal activities of the tested compounds were assessed. The inhibition rate was calculated using the following formula: inhibition rate (%) = ((fresh weight of control − fresh weight of treatment)/fresh weight of control) × 100%. The experiment was conducted from 7 March to 2 June 2024.

2.3. Crops Safety

The assay method of crop safety was similar to those previously reported [37]. Four representative crops, namely, Triticum aestivum, Zea mays, Gossypium hirsutum, and Glycine max, were selected for a crop safety study in the greenhouse. The experiment was conducted from 7 June to 19 July 2024. In brief, the seeds of the tested crops were sown in plastic pots and cultivated in a greenhouse environment. Upon reaching the four-leaf stage, the seedlings were sprayed with the test compounds BA-II-2 and BA-III-2 at a dosage of 37.5 g ha−1. The application procedure followed the methodology outlined in Section 2.2. Each treatment was repeated three times, with a one-day interval between each repetition. After a 14-day period, the crop damage caused by each compound was assessed, and the results are presented as the percentage of injury.

2.4. Phenotypic Study of Arabidopsis thaliana

Arabidopsis thaliana ecotype Columbia-0 was used for the phenotypic study. The experiment was carried out from 26 July to 14 October 2024. 5 seeds of A. thaliana were surface sterilized and sown onto half-strength Murashige and Skoog (MS) plates. The plant was grown on MS plates for two weeks from the day of sowing under LD (16 h light/8 h darkness) at 22 °C. Compound BA-II-2 and SF were dissolved in 100% DMF and then diluted with Tween-80 (concentration: 100 g/L), respectively. The resulting solutions were diluted with distilled water (pH = 7) to 0.1 mg/mL and sprayed on the surface of the plant leaves. Control plants were treated with the same amount of distilled water, DMF, and Tween 80.
The macrophenotypic study of A. thaliana was performed after seedlings treated with BA-II-2 for 3 days. Meanwhile, the leaf cell substructure of A. thaliana seedlings was analyzed using transmission electron microscopy (TEM). TEM sample preparation followed the protocol described by Houot et al. [38]. Specifically, leaf samples from control and BA-II-2-treated plantlets were excised into 1 cm2 pieces and fixed for more than 12 h in a solution containing 2.5% glutaraldehyde in water. Following fixation, the samples were washed and subsequently treated with 1.0% osmium tetroxide (OsO4) for 1.5 h. The samples were then dehydrated through a graded series of acetone washes before being embedded in epoxy resin. Ultrathin sections (70–90 nm thick) were obtained using a Reichert Ultracut S ultramicrotome and stained sequentially with uranyl acetate and lead citrate. After drying, the samples were examined under a Hitachi-7800 transmission electron microscope (Beijing, China).

2.5. Membrane Permeability Study

Membrane permeability was measured according to our previously reported method [37]. A. thaliana seedlings were treated with BA-II-2 and SF at the dosage of 150 g ha−1, respectively, and located in the greenhouse for growth. At 3, 6, 12, 24, 48, and 72 h after BA-II-2 or SF treatment, the leaves of the plants were excised at a petiole. The excised leaves were submerged in 10 mL of distilled water within a beaker and gently agitated in a water bath maintained at room temperature. After 3 h, the conductivity of the ambient solution was measured with an electric conductivity meter (DDS-307, INESA, Shanghai, China). The experiment was carried out from 28 July to 31 July 2024.

2.6. Molecular Docking

The structure of protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) from Nicotiana tabacum (PDB code: 1SEZ, NtPPO) was selected for molecular docking. The active site was determined by identifying the coordinates of the ligand OMN using Autodock tools. The structures of the target compounds BA-II-2 and SF were constructed with ChemBioDraw Ultra 12.0. Energy minimization was performed using the ChemBio3D Ultra MM2 energy minimization protocol, and the resulting structures were saved as mol2 files. These files were subsequently converted into pdbqt format using Autodock tools for molecular docking analysis. Prior to docking, water molecules and ligands were removed from the system. Kollman charges and hydrogen atoms were added to the protein structure. Molecular docking simulations between BA-II-2 or SF and NtPPO were conducted using Autodock Vina [39,40,41]. The three-dimensional structures of the resulting complexes were visualized using PYMOL [42].

2.7. Statistical Analysis

The values shown in each table are mean values ± SD of at least three repeated experiments. DPS 7.05 data processing system (DPS, Hangzhou, China) was used as a statistical software program [43,44].

3. Results and Discussion

3.1. Chemistry

The series target compounds BA-I to BA-III were prepared via an eight-step synthetic route as depicted in Scheme 1. Briefly, the nitrophenols 1a to 1f reacted with ethyl bromoacetate 2a or ethyl 4-bromobutanoate 2b or ethyl 2-bromopropanoate 2c in DMF by using K2CO3 as a base to generate series intermediates 3-I to 3-III. Then, the series intermediates 3-I to 3-III were reduced in Fe/AcOH to obtain the series intermediates 4-I to 4-III. For the synthesis of series intermediates 8-I to 8-III, intermediate 7 was first prepared through a condensation reaction of ethyl (Z)-3-amino-4,4,4-trifluorobut-2-enoate 5 and dimethylcarbamic chloride 6. Subsequently, the important series intermediates 8-I to 8-III were smoothly obtained through the condensation reaction between series intermediates 4-I to 4-III and intermediate 7. The intermediates 8-I to 8-III were methylation to the series intermediates 9-I to 9-III, which were then dissolved in an AcOH solution of H2SO4 and H2O to hydrolyze to the series intermediates 10-I to 10-III. Finally, the series intermediates 10-I to 10-III were reacted with SOCl2 under the catalytic influence of DMF to produce the corresponding acyl chlorides 11-I to 11-III. Subsequently, these acyl chlorides were allowed to react with 1,3-dimethylbarbituric acid in the presence of Et3N, yielding the corresponding series target compounds BA-I to BA-III in yields ranging from 32.9% to 75.1%. The structures of all synthesized target compounds were fully characterized using 1H NMR, 13C NMR, and HRMS.

3.2. Herbicidal Activity and SAR

As initial work, the herbicidal activity of series target compounds BA-I to BA-III was evaluated under the post-emergence conditions at a dosage of 150 g ha−1. The commercial herbicide SF was selected as the positive control. Meanwhile, the herbicidal activity of lead compound I was also evaluated to discuss SAR. As observed in Table 1, most of the newly synthesized compounds exhibited outstanding herbicidal activity, of which target compounds BA-I-2, BA-II-2, BA-III-2, and BA-III-5 exhibited complete inhibition against the tested weeds, equal to the commercial herbicide SF. Compounds BA-I-5, BA-II-3, BA-II-4, BA-II-5, and BA-III-3 also showed comparable herbicidal activity to the commercial herbicide SF, with a sum inhibition rates of 380%, 338%, 384%, 399%, and 373%, respectively. Moreover, it was found that most of the newly synthesized target compounds exhibited stronger herbicidal activity than that of lead compound I, which demonstrated that the series target compounds BA-I~BA-III were successfully designed.
Encouraged by the preliminary results, we further selected the target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) for a second round of herbicidal activity screening by using a dose reduction with a serial two-fold dilution method. As the results in Table 2 show, the herbicidal activity of the tested target compounds became progressively lower by reducing the dosage from 75 g ha−1 to 9.4 g ha−1. For instance, compound BA-I-3 demonstrates a sum inhibition rate of 220% against the tested weeds at a dose of 75 g/ha, 145% at a dose of 37.5 g/ha, 99% at a dose of 18.8 g/ha, and 49% at a dose of 9.4 g/ha; compound BA-I-5 demonstrates a sum inhibition rate of 316% against the tested weeds at a dose of 75 g/ha, 289% at a dose of 37.5 g/ha, 243% at a dose of 18.8 g/ha, and 230% at a dose of 9.4 g/ha. Although the herbicidal activity diminishes as the dose decreases, some compounds still demonstrate remarkable herbicidal efficacy even at low doses. When the dosage was reduced to 18.8 g ha−1, compounds BA-I-2, BA-II-2, BA-II-5, BA-III-2, and BA-III-5 exhibited comparable herbicidal activity to the SF (sum inhibition rate = 348%), with a sum inhibition rate of 346%, 383%, 348%, 380%, and 325%, respectively. Very promisingly, when the dosage was reduced to 9.4 g ha−1, target compounds BA-II-2 and BA-III-2 still exhibited strong herbicidal activity with a sum inhibition rate of 372% and 360%, respectively, which was significantly higher than that of SF (sum inhibition rate = 314%). These promising results indicated that target compounds BA-II-2 and BA-III-2 could be used as lead compounds for further study.
Analyzing the results shown in Table 1 and Table 2, it was found that there is some valuable SAR information. When applied at the a dosage of 150 g ha−1, target compound BA-I-2 (sum inhibition rate = 400%) exhibited 4-fold higher herbicidal activity than that of lead compound I (sum inhibition rate = 91%), implying the introduction of the pyrimidinedione moiety was beneficial to improving the herbicidal activity. Further comparisons of herbicidal activity among series target compounds BA-I at a dosage of 150 g ha−1 to reveal the effects of R1 and R2 groups on the herbicidal activity. The target compound BA-I-1 (R1 = H, R2 = H) exhibited relatively lower herbicidal activity, with a sum inhibition rate of 27%. Upon the substitution of Cl atoms at the R1 position of BA-I-1, the target compound BA-I-5 (R1 = Cl, R2 = H) demonstrated a sum inhibition rate of 380%, approximately 19-fold higher than that of BA-I-1. However, the introduction of a Cl atom at the R2 position of compound BA-I-1 did not result in any improvement in the herbicidal activity of BA-I-6 (R1 = H, R2 = Cl, sum inhibition rate = 24%). This finding indicated that the introduction of a Cl atom at the R1-position was beneficial to improving herbicidal activity.
When an F atom was introduced at the R2-position of BA-I-1, the sum inhibition rate of target compound BA-I-4 (R1 = H, R2 = F) increased to 150%. Prior research has revealed that the substitution of a hydrogen atom with a fluorine atom is considered one of the most frequently employed bioisosteric replacements in agrochemical chemistry [45,46], and the incorporation of an F atom is significant for the so-called ‘fine-tuning’ of the distribution of bioactive compounds between aqueous and lipid phases. The low polarizability of fluorine-substituted groups plays a pivotal role in improving the lipophilicity and thermal stability of compounds, which, in turn, could potentially be advantageous to bioactivity [47,48]. For instance, numerous insecticides targeting the central nervous system (CNS) include a fluorophenyl moiety, which enhances their CNS penetration and thereby contributes to their overall pharmacological activity [49]. Therefore, we speculate that compound BA-I-4 (Clog P = 3.23) exhibits higher herbicidal activity compared to BA-I-1 (Clog P = 3.04), potentially attributable to its higher Clog P value relative to BA-I-1. Comparing the herbicidal activity and Clog P among BA-I-2 and BA-I-5 verified this speculation. When introducing an F atom at the R2-position of BA-I-5 (sum inhibition rate = 380%, Clog P = 3.57), the sum inhibition rate and Clog P of target compound BA-I-2 (R1 = Cl, R2 = F) increased to 400% and 3.73, respectively. These findings indicate that increasing the lipophilicity of target compounds to a certain extent is beneficial to improving herbicidal activity. It is important to highlight that, although the Clog P values of compounds BA-I-3 (sum inhibition rate = 225%, Clog P = 4.30) and BA-I-6 (sum inhibition rate = 24%, Clog P = 3.80) are higher than those of BA-I-2 (sum inhibition rate = 400%, Clog P = 3.57) and BA-I-4 (sum inhibition rate = 150%, Clog P = 3.23), respectively, the sum inhibition rates of BA-I-3 and BA-I-6 are significantly lower than those of compounds BA-I-2 and BA-I-4, respectively. These findings suggest that hydrophobicity is not the sole determinant of improved herbicidal activity. Additionally, the type of atom at the R2 position plays a significant role in modulating herbicidal activity. Specifically, the introduction of an F atom at the R2 position enhances herbicidal activity. Taken together, the introduction of the pyrimidinedione moiety played an important effect on the herbicidal activity, and the R1 and R2 groups also had a significant effect on the herbicidal activity of target compounds, which can be placed in the following order: (R1 = Cl, R2 = F) > (R1 = Cl, R2 = H) > (R1 = Cl, R2 = Cl) > (R1 = H, R2 = F) > (R1 = H, R2= H) > (R1 = H, R2 = Cl). Notably, series target compounds BA-II and BA-III shared the same SAR as the series target compounds BA-I.
Furthermore, we performed parallel activity contrast studies among series compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) to explore the effect of alkyl side chain on the herbicidal activity. The results shown in Figure 3, when applied at the dosage of 18.8 g ha−1 (Figure 3A) or 9.4 g ha−1 (Figure 3B), the herbicidal activity of series target compounds can be placed in the following order: BA-II > BA-III > BA-I. The possible reason for this observation is that, with the extension of the alkyl chain of the target compound, the Clog P values of the compound are increased, which is conducive to the foliar absorption of the compound [50]. For instance, BA-II-2 (n = 3, R3 = H, Clog P = 4.49) exhibited good herbicidal activities against the tested weeds with a sum inhibition rate of 372% at the dose of 9.4 g ha−1, higher than that of corresponding compounds BA-III-2 (n = 1, R3 = Me, Clog P = 4.26, sum inhibition rate = 360%) and BA-I-2 (n = 1, R3 = H, Clog P = 3.73, sum inhibition rate = 283%). These results indicate that the alkyl side chain of target compounds also has an important effect on the herbicidal activity.

3.3. Herbicidal Spectrum and Crop Safety

Since target compounds BA-II-2 and BA-III-2 exhibited significantly stronger herbicidal activity than that of SF, we selected these two target compounds as representatives for a further herbicidal spectrum study at a dosage of 18.8 g ha−1 under the post-emergence conditions. As observed in Figure 4, target compound BA-II-2 exhibited strong control with inhibition >80% against 14 of the 16 weeds tested, and compound BA-III-2 displayed strong control with an inhibition rate >80% against 13 of the 16 weeds tested, while the commercial herbicide SF only showed strong control with an inhibition rate >80% against 8 of the 16 weeds tested. Additionally, compounds BA-II-2 and BA-II-3 displayed significantly stronger herbicidal acidity against B. campestris, B. tripartite, E. crus-galli, E. dahuricus, and C. virgata than that of SF (p < 0.01). These findings indicated that target compounds BA-II-2 and BA-III-2 had a broader herbicidal spectrum than that of SF. To explore whether compounds BA-II-2 and BA-III-2 have the potential to be developed as herbicides or not, their crop safety was evaluated at a dosage of 37.5 g ha−1 under the post-emergence conditions. The results shown in Table 3 revealed that T. aestivum displayed a high tolerance toward compound BA-III-2, but compound BA-III-2 was not selective for Z. mays, G. hirsutum, and G. max. For compound BA-II-2, it is unsafe for all tested crops. These promising results indicate that compound BA-III-2 can be used as a post-emergent herbicide lead compound for weed control in T. aestivum fields.

3.4. Molecular Mode of Action of the Target Compound

Due to its excellent herbicidal activity and good crop safety, compound BA-III-2 was selected as a representative for studying herbicidal mechanism using Arabidopsis thaliana as the model plant. First, the growth macrographs and the substructure of the cells of A. thaliana leaves treated with BA-III-2 were investigated. As observed in Figure 5A, A. thaliana treated with BA-III-2 developed a bleaching symptom, which is the same as that of SF. When examined with a transmission electron microscope (TEM), it was found that treatment with BA-III-2 resulted in an increase in the relative volumes of starch grains in chloroplasts of A. thaliana leaf cells (Figure 5D,E), compared with the CK (Figure 5B,C). Meanwhile, we can observe that the internal structure of the chloroplast of A. thaliana leaf cells treated with BA-III-2 was deformed, the granula lamella was loose, and even some chloroplast membranes were damaged (Figure 5F,G). Subsequently, the impact of BA-III-2 on cell membrane permeability was investigated. It was observed that electrolyte leakage from leaf cells commenced 12 h post-treatment with BA-III-2 and reached a stable state at 72 h, which is comparable to the results obtained for SF (Figure 6). These findings indicate that BA-III-2 can inhibit chlorophyll synthesis, disrupt chloroplast structure, and induce an increase in cell membrane permeability. It has been reported that PPO-inhibiting herbicides prevent the binding of protoporphyrinogen IX to the active site of protoporphyrinogen oxidase, leading to the accumulation of protoporphyrinogen IX in the cytoplasm [51,52]. Following an autooxidation process, this substrate is converted into photosensitizing protoporphyrin IX, which generates high levels of reactive oxygen species under sunlight exposure. This subsequently induces lipid peroxidation of cell membranes and results in the death of weeds [53,54]. This type of herbicide exhibits peroxidizing herbicidal symptoms characterized by rapid chlorosis, necrosis, or burning of plant tissue approximately 2–3 days after spraying in the light. In our phenotypic studies, similar phenomena were also observed in early A. thaliana leaves treated with BA-III-2. Consequently, we hypothesized that BA-III-2 might function as a PPO inhibitor.
Molecular docking is an efficient tool for predicting the interactions between ligands and receptors. To verify the above speculation, a molecular docking study was performed to confirm the interactions between BA-III-2 or SF and NtPPO. As shown in Figure 7, BA-III-2 (A) and SF (B) had some identical interacting amino acid residues, such as Arg98, Thr371, Leu372, Phe392, Leu356, Phe439, and FAD600. Among them, the pyrimidinedione rings of BA-III-2 and SF form π-π stacking interactions with Phe392, which is conserved in NtPPO enzymes. Meanwhile, Leu356 and Leu372 formed Pi-sigma bonds with the benzene ring of BA-III-2, respectively. Notably, Thr371 and Gly370 formed two H bonds with the F atom on the benzene ring of BA-III-2, and Cys177 formed one H bond with the F atom on the pyrimidinedione ring to enhance the binding with the NtPPO active cavity, which was the same for SF. These results indicated that compound BA-III-2 could combine well with NtPPO and may be a PPO inhibitor.

4. Conclusions

In summary, a series of 5-acylbarbituric acid derivatives containing a pyrimidinedione moiety were designed and synthesized. Through a systematic evaluation of the herbicidal activity of target compounds, BA-III-2 was identified as a promising herbicide lead compound owing to its exceptional herbicidal efficacy, broad-spectrum activity, and satisfactory crop safety. The study of SAR revealed that the R1 and R2 groups on the benzene ring, as well as the alkyl side chain of target compounds displayed an important effect on the herbicidal activity. The investigation into the molecular mechanism of action, through phenotypic observation and membrane permeability assessment demonstrated that treatment with BA-III-2 led to the inhibition of chlorophyll synthesis, disruption of chloroplast structure, and induction of elevated cell membrane permeability. Molecular docking revealed that BA-III-2 could combine well with NtPPO, which indicated it may be a PPO inhibitor. The present work demonstrated that BA-III-2 could serve as a lead compound for the further development of novel PPO-inhibiting herbicides. Further studies on the structural optimization of BA-III-2 are ongoing in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/agronomy15040777/s1, Figure S1: 1HNMR of the target compound BA-I-1; Figure S2: 13CNMR of the target compound BA-I-1; Figure S3: HRMS of the target compound BA-I-1; Figure S4: 1HNMR of the target compound BA-I-2; Figure S5: 13CNMR of the target compound BA-I-2; Figure S6: HRMS of the target compound BA-I-2; Figure S7: 1HNMR of the target compound BA-I-3; Figure S8: 13CNMR of the target compound BA-I-3; Figure S9: HRMS of the target compound BA-I-3; Figure S10: 1HNMR of the target compound BA-I-4; Figure S11: 13CNMR of the target compound BA-I-4; Figure S12: HRMS of the target compound BA-I-4; Figure S13: 1HNMR of the target compound BA-I-5; Figure S14: 13CNMR of the target compound BA-I-5; Figure S15: HRMS of the target compound BA-I-5; Figure S16: 1HNMR of the target compound BA-I-6; Figure S17: 13CNMR of the target compound BA-I-6; Figure S18: HRMS of the target compound BA-I-6; Figure S19: 1HNMR of the target compound BA-II-1; Figure S20: 13CNMR of the target compound BA-II-1; Figure S21: HRMS of the target compound BA-II-1; Figure S22: 1HNMR of the target compound BA-II-2; Figure S23: 13CNMR of the target compound BA-II-2; Figure S24: HRMS of the target compound BA-II-2; Figure S25: 1HNMR of the target compound BA-II-3; Figure S26: 13CNMR of the target compound BA-II-3; Figure S27: HRMS of the target compound BA-II-3; Figure S28: 1HNMR of the target compound BA-II-4; Figure S29: 13CNMR of the target compound BA-II-4; Figure S30: HRMS of the target compound BA-II-4; Figure S31: 1HNMR of the target compound BA-II-5; Figure S32: 13CNMR of the target compound BA-II-5; Figure S33: HRMS of the target compound BA-II-5; Figure S34: 1HNMR of the target compound BA-II-6; Figure S35: 13CNMR of the target compound BA-II-6; Figure S36: HRMS of the target compound BA-II-6; Figure S37: 1HNMR of the target compound BA-III-1; Figure S38: 13CNMR of the target compound BA-III-1; Figure S39: HRMS of the target compound BA-III-1; Figure S40: 1HNMR of the target compound BA-III-2; Figure S41: 13CNMR of the target compound BA-III-2; Figure S42: HRMS of the target compound BA-III-2; Figure S43: 1HNMR of the target compound BA-III-3; Figure S44: 13CNMR of the target compound BA-III-3; Figure S45: HRMS of the target compound BA-III-3; Figure S46: 1HNMR of the target compound BA-III-4; Figure S47: 13CNMR of the target compound BA-III-4; Figure S48: HRMS of the target compound BA-III-4; Figure S49: 1HNMR of the target compound BA-III-5; Figure S50: 13CNMR of the target compound BA-III-5; Figure S51: HRMS of the target compound BA-III-5; Figure S52: 1HNMR of the target compound BA-III-6; Figure S53: 13CNMR of the target compound BA-III-6; Figure S54: HRMS of the target compound BA-III-6.

Author Contributions

Conceptualization, R.L. and K.L.; methodology, R.L. and K.L.; validation, K.C.; formal analysis, K.C. and S.F.; investigation, K.C. and S.W.; data curation, S.W., S.F. and K.C.; writing—original draft preparation, K.C.; writing—review and editing, J.K. and P.P.; project administration, W.G., J.K. and P.P.; funding acquisition, K.L. and W.G. 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 and 32402430); the Natural Science Foundation of Shandong Province (No. ZR2023MC095); 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.

References

  1. Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A. Current challenges and trends in the discovery of agrochemicals. Science 2013, 341, 742–746. [Google Scholar] [CrossRef] [PubMed]
  2. Westwood, J.H.; Charudattan, R.; Duke, S.O.; Fennimore, S.A.; Marrone, P.; Slaughter, D.C.; Swanton, C.; Zollinger, R. Weed management in 2050: Perspectives on the future of weed science. Weed Sci. 2018, 66, 275–285. [Google Scholar]
  3. Ofosu, R.; Agyemang, E.D.; Márton, A.; Pásztor, G.; Taller, J.; Kazinczi, G. Herbicide resistance: Managing weeds in a changing world. Agronomy 2023, 13, 1595. [Google Scholar] [CrossRef]
  4. Zhang, P.; Duan, C.B.; Jin, B.; Ali, A.S.; Han, X.Y.; Zhang, H.F.; Zhang, M.Z.; Zhang, W.H.; Gu, Y.C. Recent advances in the natural products-based lead discovery for new agrochemicals. Adv. Agrochem. 2023, 2, 324–339. [Google Scholar] [CrossRef]
  5. Marrone, P.G. Pesticidal natural products-status and future potential. Pest Manag. Sci. 2019, 75, 2325–2340. [Google Scholar] [CrossRef]
  6. Gerwick, B.C.; Sparks, T.C. Natural products for pest control: An analysis of their role, value and future. Pest Manag. Sci. 2014, 70, 1169–1185. [Google Scholar]
  7. Ahrens, H.; Lange, G.; Müller, T.; Rosinger, C.; Willms, L.; van Almsick, V. 4-Hydroxyphenylpyruvate dioxygenase inhibitors in combination with safeners: Solutions for modern and sustainable agriculture. Angew. Chem. Int. Ed. 2013, 52, 9388–9398. [Google Scholar] [CrossRef]
  8. Dayan, F.E.; Owens, D.K.; Duke, S.O. Rationale for a natural products approach to herbicide discovery. Pest Manag. Sci. 2012, 68, 519–528. [Google Scholar] [CrossRef]
  9. Nadia, A.A.E.; Hajer, H. Mini review on synthesis of pyrimidinthione, pyrimidinedione derivatives and their biological activity. Recent Adv. Petrochem. Sci. 2018, 6, 555676. [Google Scholar]
  10. Grossmann, K.; Niggeweg, R.; Christiansen, N.; Looser, R.; Ehrhardt, T. The herbicide saflufenacil (kixorTM) is a new inhibitor of protoporphyrinogen ix oxidase activity. Weed Sci. 2010, 58, 1–9. [Google Scholar] [CrossRef]
  11. Singh, N.; Shreshtha, A.K.; Thakur, M.S.; Patra, S. Xanthine scaffold: Scope and potential in drug development. Heliyon 2018, 4, e00829. [Google Scholar]
  12. Zhang, F.; Braun, D.R.; Ananiev, G.E.; Hoffmann, F.M.; Tsai, I.W.; Rajski, S.R.; Bugni, T.S. Biemamides A-E, inhibitors of the TGF-β pathway that block the epithelial to mesenchymal transition. Org. Lett. 2018, 20, 5529–5532. [Google Scholar]
  13. Dewal, M.B.; Wani, A.S.; Vidaillac, C.; Oupický, D.; Rybak, M.J.; Firestine, S.M. Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents. Eur. J. Med. Chem. 2012, 51, 145–153. [Google Scholar]
  14. Lin, X.; Kurz, J.L.; Patel, K.M.; Wun, S.J.; Hussein, W.M.; Lonhienne, T.; West, N.P.; McGeary, R.P.; Schenk, G.; Guddat, L.W. Discovery of a pyrimidine-dione derivative with potent inhibitory activity against Mycobacterium tuberculosis ketol-acid reductoisomerase. Chem. Eur. J. 2021, 27, 3130–3141. [Google Scholar]
  15. Buckheit, K.W.; Yang, L.; Buckheit, R.W., Jr. Development of dual-acting pyrimidinediones as novel and highly potent topical anti-HIV microbicides. Antimicro. Agents Chemother. 2011, 55, 5243–5254. [Google Scholar]
  16. El-Sherbeny, M.; El-Ashmawy, M.; El-Subbagh, H.; El-Emam, A.; Badria, F. Synthesis, antimicrobial and antiviral evaluation of certain thienopyrimidine derivatives. Eur. J. Med. Chem. 1995, 30, 445–449. [Google Scholar]
  17. Mitchell, M.L.; Son, J.C.; Guo, H.Y.; Im, Y.A.; Cho, E.J.; Wang, J.H.; Hayes, J.; Wang, M.; Paul, A.; Lansdon, E.B.; et al. N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2010, 20, 1589–1592. [Google Scholar]
  18. Loksha, Y.M.; Pedersen, E.B.; Loddo, R.; Sanna, G.; Collu, G.; Giliberti, G.; Colla, P.L. Synthesis of novel fluoro analogues of mkc442 as microbicides. J. Med. Chem. 2014, 57, 5169–5178. [Google Scholar]
  19. Zhang, H.; Peng, X.; Dai, Y.; Shao, J.; Ji, Y.; Sun, Y.; Liu, B.; Cheng, X.; Ai, J.; Duan, W. Discovery of a pyrimidinedione derivative as a potent and orally bioavailable Axl inhibitor. J. Med. Chem. 2021, 64, 3956–3975. [Google Scholar]
  20. Aknin, K.; Bontemps, A.; Farce, A.; Merlet, E.; Belmont, P.; Helissey, P.; Chavatte, P.; Sari, M.A.; Giorgi-Renault, S.; Desbene-Finck, S. Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: Synthesis, biological evaluation, and molecular docking study. J. Enzyme Inhib. Med. Chem. 2022, 37, 252–268. [Google Scholar]
  21. Günther, J.; Hillig, R.C.; Zimmermann, K.; Kaulfuss, S.; Lemos, C.; Nguyen, D.; Rehwinkel, H.; Habgood, M.; Lechner, C.; Neuhaus, R.; et al. BAY-069, a novel (trifluoromethyl)pyrimidinedione-based bcat1/2 inhibitor and chemical probe. J. Med. Chem. 2022, 65, 14366–14390. [Google Scholar]
  22. Guile, S.D.; Bantick, J.R.; Cooper, M.E.; Donald, D.K.; Eyssade, C.; Ingall, A.H.; Lewis, R.J.; Martin, B.P.; Mohammed, R.T.; Potter, T.J.; et al. Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties. J. Med. Chem. 2007, 50, 254–263. [Google Scholar]
  23. Jha, V.; Bhadoriya, K.S. Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents. J. Mol. Struct. 2018, 1158, 96–105. [Google Scholar]
  24. Zhang, Z.Y.; Wallace, M.B.; Feng, J.; Stafford, J.A.; Skene, R.J.; Shi, L.H.; Lee, B.; Aertgeerts, K.; Jennings, A.; Xu, R.D.; et al. Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV. J. Med. Chem. 2011, 54, 510–524. [Google Scholar]
  25. Li, N.; Wang, L.J.; Jiang, B.; Guo, S.J.; Li, X.Q.; Chen, X.C.; Luo, J.; Li, C.; Wang, Y.; Shi, D.Y. Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors. Bioorg. Med. Chem. Lett. 2018, 28, 2131–2135. [Google Scholar]
  26. Park, J.; Ahn, Y.O.; Nam, J.-W.; Hong, M.-K.; Song, N.; Kim, T.; Yu, G.-H.; Sung, S.-K. Biochemical and physiological mode of action of tiafenacil, a new protoporphyrinogen ix oxidase-inhibiting herbicide. Pestic. Biochem. Phys. 2018, 152, 38–44. [Google Scholar]
  27. Lee, W.H.; Kwon, Y.B.; Lee, K.H.; Choi, J.S.; Seu, Y.B. Synthesis of cyclopropyl ester and amide substituted pyrimidinediones as protoporphyrinogen oxidase-inhibiting herbicides. Bull. Korean Chem. Soc. 2021, 42, 420–428. [Google Scholar]
  28. Lee, W.H.; Kwon, Y.B.; Kim, J.H.; Lee, K.H.; Maezono, S.M.B.; Choi, J.S.; Seu, Y.B. Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as potential PPO herbicides. Bioorg. Med. Chem. 2021, 31, 115959. [Google Scholar]
  29. Wang, D.W.; Zhang, R.B.; Ismail, I.; Xue, Z.Y.; Liang, L.; Yu, S.Y.; Wen, X.; Xi, Z. Design, herbicidal activity, and QSAR analysis of cycloalka[d]quinazoline-2,4-dione-benzoxazinones as protoporphyrinogen IX oxidase inhibitors. J. Agric. Food Chem. 2019, 67, 9254–9264. [Google Scholar]
  30. Wang, D.W.; Zhang, H.; Yu, S.Y.; Zhang, R.B.; Liang, L.; Wang, X.; Yang, H.Z.; Xi, Z. Discovery of a potent thieno[2,3-d]pyrimidine-2,4-dione-based protoporphyrinogen IX oxidase inhibitor through an in silico structure-guided optimization approach. J. Agric. Food Chem. 2021, 69, 14115–14125. [Google Scholar]
  31. Wang, D.W.; Lin, H.Y.; Cao, R.J.; Ming, Z.Z.; Chen, T.; Hao, G.F.; Yang, W.C.; Yang, G.F. Design, synthesis and herbicidal activity of novel quinazoline-2,4-diones as 4-hydroxyphenylpyruvate dioxygenase inhibitors. Pest Manag. Sci. 2015, 71, 1122–1132. [Google Scholar]
  32. Wang, D.W.; Lin, H.Y.; Cao, R.J.; Yang, S.G.; Chen, Q.; Hao, G.F.; Yang, W.C.; Yang, G.F. Synthesis and herbicidal evaluation of triketone-containing quinazoline-2,4-diones. J. Agric. Food Chem. 2014, 62, 11786–11796. [Google Scholar]
  33. Lei, K.; Li, P.; Zhou, X.; Wang, S.; Wang, X.; Ji, L.; Liu, R.; Xu, X. Design, synthesis and herbicidal activity of 5-acylbarbituric acid derivatives and study of molecular mode of action. Chin. J. Org. Chem. 2020, 40, 2788–2797. [Google Scholar]
  34. Lei, K.; Li, P.; Yang, X.F.; Wang, S.B.; Wang, X.K.; Hua, X.W.; Sun, B.; Ji, L.S.; Xu, X.H. Design and synthesis of novel 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives for use as herbicides and evaluation of their mode of action. J. Agric. Food Chem. 2019, 67, 10489–10497. [Google Scholar]
  35. Wang, C.D.; Qing, X.S.; Wang, T.; Dai, C.L.; Su, Z.J. Direct synthesis of 6H-chromeno[3,4-b]quinolin-6-ol derivatives from substituted 3-nitro-2H-chromenes and 2-nitrobenzaldehydes mediated by Fe/AcOH system. Synthesis 2018, 50, 1350–1358. [Google Scholar]
  36. Yang, J.C.; Guan, A.Y.; Wu, Q.; Cui, D.L.; Liu, C.L. Design, synthesis and herbicidal evaluation of novel uracil derivatives containing an isoxazoline moiety. Pest Manag. Sci. 2020, 76, 3395–3402. [Google Scholar]
  37. Li, N.; Chen, K.; Han, S.B.; Wang, S.M.; He, Y.Q.; Wang, X.K.; Li, P.; Ji, L.S.; Liu, R.; Lei, K. Synthesis, herbicidal activity, and molecular mode of action evaluation of novel aryloxyphenoxypropionate/amide derivatives containing a quinazolinone moiety. J. Agric. Food Chem. 2024, 72, 9445–9456. [Google Scholar]
  38. Houot, V.; Etienne, P.; Petitot, A.; Barbier, S.; Blein, J.; Suty, L. Hydrogen peroxide induces programmed cell death features in cultured tobacco BY-2 cells, in a dose-dependent manner. J. Exp. Bot. 2001, 52, 1721–1730. [Google Scholar]
  39. Trott, O.; Olson, A.J. Autodock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comp. Chem. 2010, 31, 455–461. [Google Scholar]
  40. Tanchuk, V.Y.; Tanin, V.O.; Vovk, I.; Poda, G. A new improved hybrid scoring function for molecular docking and scoring based on autodock and autodock vina. Chem. Biol. Drug Des. 2016, 87, 618–625. [Google Scholar]
  41. Di, M.E.; Toti, D.; Polticelli, F. Dockingapp: A user friendly interface for facilitated docking simulations with autodock vina. J. Comput. Aid. Mol. Des. 2017, 31, 213–218. [Google Scholar]
  42. Chaudhari, R.; Li, Z. Pymine: A pymol plugin to integrate and visualize data for drug discovery. BMC Res. Not. 2015, 8, 517. [Google Scholar]
  43. Tang, Q.Y.; Zhang, C.X. Data Processing System (DPS) software with experimental design, statistical analysis and data mining developed for use in entomological research. Insect Sci. 2013, 20, 254–260. [Google Scholar]
  44. Tang, Q.Y.; Lin, Y.X. Maximum entropy-minimum residual model: An optimum solution to comprehensive evaluation and multiple attribute decision making. Entropy 2025, 27, 203. [Google Scholar] [CrossRef]
  45. O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 2008, 37, 308–319. [Google Scholar]
  46. Ogawa, Y.; Tokunaga, E.; Kobayashi, O.; Hirai, K.; Shibata, N. Current contributions of organofluorine compounds to the agrochemical industry. iScience 2020, 23, 101467. [Google Scholar]
  47. Ojima, I. Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology. J. Org. Chem. 2013, 78, 6358–6383. [Google Scholar]
  48. Rao, W.J.; Li, M.L.; You, X.L.; Wei, Z.H.; Zhang, M.X.; Wang, L.Y.; Cai, H. The role of fluorine-substituted positions on the phase rransition in organic–inorganic hybrid perovskite compounds. Inorg. Chem. 2021, 60, 14706–14712. [Google Scholar]
  49. Jeschke, P. The unique role of halogen substituents in the design of modern agrochemicals. Pest Manag. Sci. 2010, 66, 10–27. [Google Scholar]
  50. Yan, Z.Z.; Yang, Z.H.; Deng, X.L.; Lin, D.; Wu, M.F.; Li, J.M.; Chen, A.Y.; Ye, J.; Hu, A.X.; Liao, H.D. Novel aryloxyphenoxypropionate derivates containing benzofuran moiety: Design, synthesis, herbicidal activity, docking study and theoretical calculation. Pestic. Biochem. Physiol. 2019, 154, 78–87. [Google Scholar]
  51. Zuo, Y.; Wu, Q.; Su, S.W.; Niu, C.W.; Xi, Z.; Yang, G.F. Synthesis, herbicidal activity, and QSAR of novel N-benzothiazolylpyrimidine-2,4-diones as protoporphyrinogen oxidase inhibitors. J. Agric. Food Chem. 2016, 64, 552–562. [Google Scholar] [PubMed]
  52. Zhao, L.X.; Jiang, M.J.; Hu, J.J.; Zou, Y.L.; Cheng, Y.; Ren, T.; Gao, S.; Fu, Y.; Ye, F. Design, synthesis, and herbicidal activity of novel diphenyl ether derivatives containing fast degrading tetrahydrophthalimide. J. Agric. Food Chem. 2020, 68, 3729–3741. [Google Scholar]
  53. Qin, X.; Sun, L.; Wen, X.; Yang, X.; Tan, Y.; Jin, H.; Cao, Q.; Zhou, W.; Xi, Z.; Shen, Y. Structural insight into unique properties of protoporphyrinogen oxidase from Bacillus subtilis. J. Struct. Biol. 2010, 170, 76–82. [Google Scholar]
  54. Wang, B.; Wen, X.; Xi, Z. Molecular simulations bring new insights into protoporphyrinogen IX oxidase/protoporphyrinogen IX interaction modes. Mol. Inf. 2016, 35, 476–482. [Google Scholar]
Agronomy 15 00777 g001
Figure 1. Design of series target compounds BA.
Figure 1. Design of series target compounds BA.
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Scheme 1. General synthetic route of series target compounds BA-I~BA-III.
Scheme 1. General synthetic route of series target compounds BA-I~BA-III.
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Figure 2. The structures of series target compounds BA-I to BA-III.
Figure 2. The structures of series target compounds BA-I to BA-III.
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Figure 3. (A): Parallel activity contrast among series target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) at a dosage of 18.8 g ha−1; (B): Parallel activity contrast among series target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) at a dosage of 9.4 g ha−1.
Figure 3. (A): Parallel activity contrast among series target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) at a dosage of 18.8 g ha−1; (B): Parallel activity contrast among series target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) at a dosage of 9.4 g ha−1.
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Figure 4. Herbicidal spectrum testing of compounds BA-II-2 and BA-III-2 under the post-emergence conditions at a dosage of 18.8 g ha−1; Different letters represent significant differences between the treatments (p < 0.01). Abbreviations: BC: B. campestris, AT: A. tricolor, LI: L. indica, PO: P. oleracea, TM: T. mongolicum, CA: C. album, BT: B. tripartita, IN: I. nil, EC: E. crus-galli, DS: D. sanguinalis, SV: S. viridis, EI: E. indica, SA: S. alterniflora, PA: P. alopecuroides, CA: C. virgata, and ED: E. dahuricus.
Figure 4. Herbicidal spectrum testing of compounds BA-II-2 and BA-III-2 under the post-emergence conditions at a dosage of 18.8 g ha−1; Different letters represent significant differences between the treatments (p < 0.01). Abbreviations: BC: B. campestris, AT: A. tricolor, LI: L. indica, PO: P. oleracea, TM: T. mongolicum, CA: C. album, BT: B. tripartita, IN: I. nil, EC: E. crus-galli, DS: D. sanguinalis, SV: S. viridis, EI: E. indica, SA: S. alterniflora, PA: P. alopecuroides, CA: C. virgata, and ED: E. dahuricus.
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Agronomy 15 00777 g005
Figure 5. Phenotype of A. thaliana seedlings (A) and TEM images of A. thaliana leaf cells (control: (B,C); treated with BA-III-2: (D–G)).
Figure 5. Phenotype of A. thaliana seedlings (A) and TEM images of A. thaliana leaf cells (control: (B,C); treated with BA-III-2: (D–G)).
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Agronomy 15 00777 g006
Figure 6. Effect of BA-III-2 and SF on leaf cell permeability as determined by changes in the electrical conductance of the surrounding solution.
Figure 6. Effect of BA-III-2 and SF on leaf cell permeability as determined by changes in the electrical conductance of the surrounding solution.
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Agronomy 15 00777 g007
Figure 7. (A) Docking three-dimensional diagram between BA-III-2 and NtPPO; (B) Docking three-dimensional diagram between SF and NtPPO; (C) Docking two-dimensional diagram between BA-III-2 and NtPPO; (D) Docking two-dimensional diagram between SF and NtPPO.
Figure 7. (A) Docking three-dimensional diagram between BA-III-2 and NtPPO; (B) Docking three-dimensional diagram between SF and NtPPO; (C) Docking two-dimensional diagram between BA-III-2 and NtPPO; (D) Docking two-dimensional diagram between SF and NtPPO.
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Table 1. Effects (% inhibition) of the series target compounds BA-I~BA-III on the loss of plant weight at the dosage of 150 g ha−1 under the post-emergence condition 1.
Table 1. Effects (% inhibition) of the series target compounds BA-I~BA-III on the loss of plant weight at the dosage of 150 g ha−1 under the post-emergence condition 1.
Comp.B. campestrisA. tricolorE. crusgalliD. sanguinalisSum Inhibition 2
BA-I-14 ± 2 Ii16 ± 5 Fef0 Gh7 ± 2 Ij27
BA-I-2100 Aa100 Aa100 Aa100 Aa400
BA-I-333 ± 3 Gg79 ± 5 Dc52 ± 2 Dd61 ± 2 De225
BA-I-433 ± 7 Gg66 ± 6 Ed30 ± 7 Ef21 ± 2 Gh150
BA-I-591 ± 2 ABCb96 ± 4 ABab97 ± 3 Aa96 ± 1 Aab380
BA-I-60 Ii18 ± 3 Fe0 Gh7 ± 2 Ij24
BA-II-139 ± 3 Gf90 ± 3 BCb46 ± 7 De60 ± 6 De236
BA-II-2100 Aa100 Aa100 Aa100 Aa400
BA-II-383 ± 2 DEd100 Aa74 ± 1 Bb82 ± 3 Bc338
BA-II-490 ± 3 CDbc100 Aa99 ± 1 Aa96 ± 3 Aab384
BA-II-599 ± 2 ABa100 Aa100 Aa100 Aa399
BA-II-60 Ii66 ± 5 Ed1 ± 0 Gh13 ± 3 Hi80
BA-III-161 ± 2 Fe81 ± 3 Dc22 ± 5 Fg33 ± 2 Fg196
BA-III-2100 Aa100 Aa100 Aa100 Aa400
BA-III-384 ± 5 CDEcd90 ± 1 BCb98 ± 3 Aa100 Aa373
BA-III-478 ± 6 Ed84 ± 4 CDc60 ± 3 Cc67 ± 3 Cd290
BA-III-5100 Aa100 Aa100 Aa100 Aa400
BA-III-62 ± 6 Ii12 ± 5 Ff51 ± 1 Dde45 ± 5 Ef110
I22 ± 7 Hh64 ± 7 Ed0 Gh5 ± 1 Ij91
SF100 Aa100 Aa100 Aa100 Aa400
1 Each value represents the mean ± SD of three experiments; different uppercase letters represent significant differences between different treatments (p < 0.01), and different lowercase letters represent significant differences between different treatments (p < 0.05); 2 each value represents the summation of the target compound’s mean of three experiments against each individual weed species.
Table 2. Effects (% inhibition) of the target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) on the loss of plant weight at a different dosage in greenhouse testing 1.
Table 2. Effects (% inhibition) of the target compounds BA-I-(2-5), BA-II-(2-5), and BA-III-(2-5) on the loss of plant weight at a different dosage in greenhouse testing 1.
Comp.Dosage (g ha−1)BCARECDSSum Inhibition 2
BA-I-275100 Aa97 ± 2 Aa98 ± 2 Aa96 ± 4 ABab391
37.599 ± 1 Aa98 ± 4 Aa93 ± 3 ABb97 ± 3 Aab386
18.883 ± 3 Dd96 ± 4ABab84 ± 3 BCb84 ± 3 ABCbc346
9.483 ± 5 BCbc95 ± 4 Aa45 ± 1 Cd61 ± 4 Ccd283
BA-I-37537 ± 5 Ee68 ± 6 Dd53 ± 5 Ff62 ± 7 De220
37.534 ± 3 Fg55 ± 1 Ee18 ± 1 Gh38 ± 5 Def145
18.828 ± 6 Ff51 ± 3 DEe5 ± 2 Gfg14 ± 2 Hh99
9.410 ± 1 Ee39 ± 4 Ee0 Fg0 Gh49
BA-I-47513 ± 2 Ff41 ± 3 Ee18 ± 4 Hh11 ± 2 Fg83
37.511 ± 3 Gh21 ± 3 Ff6 ± 5 Hi7 ± 6 Eg45
18.85 ± 3 Hh13 ± 4 Ff0 Gg0 Ii18
9.40 Ff3 ± 2 Hh0 Fg0 Gh3
BA-I-57597 ± 4 Aa83 ± 5 BCb85 ± 5 Cc51 ± 6 Ef316
37.597 ± 3 Aa84 ± 3 Bb63 ± 2 De44 ± 8 De289
18.891 ± 4 BCDbc78 ± 6 Cc28 ± 7 Fe46 ± 5 Ff243
9.488 ± 4 Bb76 ± 4 CDc32 ± 5 De35 ± 6 De230
BA-II-275100 Aa100 Aa100 Aa100 Aa400
37.5100 Aa100 Aa100 Aa98 ± 2 Aa398
18.897 ± 1 ABCab100 Aa95 ± 1 Aa91 ± 2 Aa383
9.496 ± 1 Aa100 Aa89 ± 2 Aa88 ± 3 Aa372
BA-II-37587 ± 4 Bb100 Aa90 ± 2 BCb91 ± 3 Bb368
37.561 ± 3 Dd100 Aa81 ± 4 Cc88 ± 3 Ab330
18.859 ± 8 Ee92 ± 3 ABb60 ± 6 Dc74 ± 7 DEde286
9.448 ± 2 Dd84 ± 4 BCb44 ± 4 Cd57 ± 6 Ccd233
BA-II-47575 ± 4 Cc87 ± 1 Bb67 ± 5 Ee74 ± 3 Cd302
37.553 ± 5 Ee81 ± 5 Bcb41 ± 9 Ef56 ± 7 Cd231
18.834 ± 6 Ff57 ± 6 Dd23 ± 7 Fe26 ± 1 Gg140
9.47 ± 4 Ee25 ± 2 Ff2 ± 1 Fg7 ± 1 Fg41
BA-II-57595 ± 2 Aa100 Aa96 ± 1 ABa92 ± 3 Bb382
37.588 ± 3 Bb99 ± 3 Aa91 ± 3 Bb96 ± 4 Aab373
18.891 ± 2 BCDbc100 Aa77 ± 4 Cb80 ± 5 BCDcd348
9.485 ± 3 BCb97 ± 5 Aa50 ± 2 Ccd63 ± 6 Cc295
BA-III-275100 Aa100 Aa100 Aa100 Aa400
37.5100 Aa100 Aa100 Aa96 ± 6 Aab396
18.8100 Aa100 Aa92 ± 1 Aba87 ± 4 ABab380
9.4100 Aa97 ± 6 Aa86 ± 6 ABa77 ± 5 Bb360
BA-III-37582 ± 5 BCb77 ± 4 Cc76 ± 3 Dd79 ± 4 Cc314
37.578 ± 5 Cc76 ± 6 Cc75 ± 1 Cd74 ± 2 Bc303
18.858 ± 6 Ee73 ± 2 Cc48 ± 4 Ed46 ± 3 Ff224
9.445 ± 4 Dd67 ± 6 Dd16 ± 4 Ef22 ± 5 Ef150
BA-III-47555 ± 5 Dd71 ± 1 Dd41 ± 4 Gg53 ± 5 Ef221
37.540 ± 3 Ff63 ± 7 Dd33 ± 5 Fg35 ± 5 Df171
18.817 ± 3 Gg45 ± 5 Ee9 ± 2 Gf11 ± 2 Hh82
9.48 ± 3 Ee12 ± 4 Gg0 Fg3 ± 2 FGgh23
BA-III-575100 Aa100 Aa100 Aa100 Aa400
37.5100 Aa98 ± 4 Aa96 ± 2 ABab95 ± 6 Aab388
18.899 ± 1 ABa91 ± 2 Bb66 ± 2 Dc68 ± 6 Ee325
9.484 ± 3 BCbc86 ± 5 Bb54 ± 2 Cc55 ± 4 Cd278
SF75100 Aa100 Aa100 Aa100 Aa400
37.5100 Aa100 Aa100 Aa100 Aa400
18.889 ± 3 CDcd100 Aa84 ± 3 BCb75 ± 2 CDEd348
9.478 ± 4 Cc97 ± 4 Aa77 ± 5 Bb63 ± 1 Cc314
1 Each value represents the mean ± SD of three experiments; different uppercase letters represent significant differences between different treatments (p < 0.01), and different lowercase letters represent significant differences between different treatments (p < 0.05); 2 each value represents the summation of the target compound’s mean of three experiments against each individual weed species.
Table 3. Post-emergence crop selectivity of compounds BA-II-2, BA-III-2, and SF at the dosage of 37.5 g ha−1 (Injury %) 1.
Table 3. Post-emergence crop selectivity of compounds BA-II-2, BA-III-2, and SF at the dosage of 37.5 g ha−1 (Injury %) 1.
Comp.Injury (%)
T. aestivumZ. maysG. hirsutumG. max
BA-II-236 ± 5 Aa49 ± 7 Aa52 ± 2 Bb100 Aa
BA-III-25 ± 1 Bb27 ± 4 ABb42 ± 2 Cc100 Aa
SF7 ± 3 Bb15 ± 2 Bb100 Aa62 ± 4 Bb
1 Each value represents the mean ± SD of three experiments; different uppercase letters represent significant differences between different treatments (p < 0.01), and different lowercase letters represent significant differences between different treatments (p < 0.05).
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Chen, K.; Wang, S.; Fu, S.; Gao, W.; Kim, J.; Park, P.; Liu, R.; Lei, K. Design, Synthesis, and Herbicidal Activity of Novel 5-Acylbarbituric Acid Derivatives Containing a Pyrimidinedione Moiety. Agronomy 2025, 15, 777. https://doi.org/10.3390/agronomy15040777

AMA Style

Chen K, Wang S, Fu S, Gao W, Kim J, Park P, Liu R, Lei K. Design, Synthesis, and Herbicidal Activity of Novel 5-Acylbarbituric Acid Derivatives Containing a Pyrimidinedione Moiety. Agronomy. 2025; 15(4):777. https://doi.org/10.3390/agronomy15040777

Chicago/Turabian Style

Chen, Ke, Shumin Wang, Shuyue Fu, Wei Gao, Junehyun Kim, Phumbum Park, Rui Liu, and Kang Lei. 2025. "Design, Synthesis, and Herbicidal Activity of Novel 5-Acylbarbituric Acid Derivatives Containing a Pyrimidinedione Moiety" Agronomy 15, no. 4: 777. https://doi.org/10.3390/agronomy15040777

APA Style

Chen, K., Wang, S., Fu, S., Gao, W., Kim, J., Park, P., Liu, R., & Lei, K. (2025). Design, Synthesis, and Herbicidal Activity of Novel 5-Acylbarbituric Acid Derivatives Containing a Pyrimidinedione Moiety. Agronomy, 15(4), 777. https://doi.org/10.3390/agronomy15040777

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