Discovery of Novel N-Pyridylpyrazole Thiazole Derivatives as Insecticide Leads

Abstract

To develop effective insecticides against Lepidoptera pests, 25 novel N-pyridylpyrazole derivatives containing thiazole moiety were designed and synthesized based on the intermediate derivatization method (IDM). The insecticidal activities of these target compounds against Plutella xylostella (P. xylostella), Spodoptera exigua (S. exigua), and Spodoptera frugiperda (S. frugiperda) were evaluated. Bioassays indicated that compound 7g−7j exhibited good insecticidal activities. Compound 7g showed especially excellent insecticidal activities against P. xylostella, S. exigua, and S. frugiperda with LC₅₀ values of 5.32 mg/L, 6.75 mg/L, and 7.64 mg/L, respectively, which were adequate for that of commercial insecticide indoxacarb. A preliminary structure-activity relationship analysis showed that the insecticidal activities of thiazole amides were better than that of thiazole esters, and the amides with electron-withdrawing groups on the benzene ring were better than the ones with electron-donating groups. This work provides important information for designing novel N-pyridylpyrazole thiazole candidate compounds and suggests that the 7g is a promising insecticide lead for further studies.

1. Introduction

As the world’s population continues to grow, food shortages will become increasingly prominent in the future, especially in underdeveloped or remote areas. Agricultural pests are the main threat to crop production: approximately 20~40 percent of crop losses each year are caused by plant diseases and insect pests [1,2]. Lepidoptera pests, such as Plutella xylostella (P. xylostella) and Spodoptera frugiperda (S. frugiperda) have a short reproductive cycle, high reproductive rate, and serious overlap of generations, which bring a great burden to agricultural producers [3,4]. Many efforts have been devoted to the development of effective control methods against these pests, such as agricultural, physical, biological, and chemical controls. Among them, chemical control with insecticides remains the major method due to its high efficacy and economic efficiency. However, the long-term and unreasonable use of chemical insecticides has brought up problems such as environmental issues and resistance to pests [5,6]. Therefore, it is necessary to discover insecticidal structures with novel scaffolds that should be environmentally safe, with less impact on non-target species and human health, which is a hot spot in current pesticide research [7,8].

Traditionally, it takes about ten years and over USD 256 million to develop a new agrochemical [9]. Several practical strategies have been proposed to enhance the probability of success, such as modification of natural compounds [10], scaffold-hopping [11], “Me Too” chemistry [12], and IDM [13]. In particular, the IDM emphasizing the functionalization of intermediates of agrochemical with facile and economical synthetic methods has received more attention [14,15,16].

N-pyridylpyrazoles are heterocyclic structures widely applied in the field of agrochemicals. DuPont developed chlorantraniliprole as the first commercial insecticide with N-pyridylpyrazole, and its molecular targets were identified to be insect ryanodine receptors (RyRs), located in the sarcoplasmic reticulum and endoplasmic reticulum membranes and are homotetrameric intracellular calcium (Ca²⁺) release channels that play a critical role in the excitation-contraction coupling of muscle [17]. Since then, N-pyridylpyrazole derivatives have been successfully developed and commercialized to act on RyRs, such as cyantraniliprole [18], tetraniliprole [19], cyclaniliprole [20], and tetrachlorantraniliprole [21] (Figure 1). In addition, numerous structure modifications and optimizations have been conducted on the N-pyridylpyrazole scaffold to acquire new insecticide candidates with improved properties [22,23,24,25].

Thiazole is an important heterocyclic structure widely applied in commercial pesticides, such as insecticides (e.g., thiamethoxam and clothianidin, nicotinic acetylcholine receptor competitive regulator), nematicide (e.g., fluensulfone, metabolic inhibitors of energy storage processes), and fungicides (e.g., thifluzamide, thiabendazole, and ethaboxam) (Figure 1). In our previous work, a series of thiazolyl substituted sulfonamides were found to exhibit good insecticidal or fungicidal activities [26]. These examples indicate that thiazole is an effective scaffold for designing a novel lead compound in the drug discovery process. Although thiazole scaffolds have been widely used in the field of pesticides, they are only some fungicides and commercial pesticides for controlling piercing-sucking pests, but fewer pesticides containing thiazole scaffolds for controlling chewing pests have been marketed [27,28,29]. Therefore, introducing a thiazole ring into insecticide fragments to control chewing pests is an interesting topic. In addition, amide and ester structures are widely used in the development of pesticides, because the introduction of amide and ester groups can enhance the interaction between drug molecules and receptors, leading to chemical molecules exhibiting significant insecticidal, nematocidal, and other bioactivities [30,31,32].

To obtain novel N-pyridylpyrazole thiazole derivatives with potential insecticidal activity, we sought to retain the substructure of N-pyridylpyrazole, and increase the amide bridge by introducing a thiazole moiety based on the IDM (Figure 2). A series of N-pyridylpyrazole derivatives containing thiazoles were designed and synthesized. Structures of all synthesized compounds were characterized by ¹ H NMR and ¹³ C NMR. Insecticidal activities of the target compounds were evaluated against P. xylostella, S. exigua, and S. frugiperda, and preliminary structure-activity relationship (SAR) was discussed.

2. Materials and Methods

2.1. Instrumentation and Chemicals

The chemical reagents and solvents, purchased from commercial sources (Energy Chemical, Shanghai, China) were used without further purification. Column chromatography purification was performed using silica gel (silica gel 200−300 mesh and 300−400 mesh, Qingdao Makall Group Co., Ltd., Qingdao, China). ¹H NMR and ¹³C NMR were recorded with AV-600 MHz (Bruker, Billerica, MA, USA), and the chemical shifts were reported in ppm from the solvent resonance as the internal standard (CDCl₃ δ_H: 7.26 ppm, δ_C: 77.16 ppm; DMSO-d₆ δ_H: 2.50 ppm, δ_C: 39.51 ppm). MS (ESI) data were recorded on an AB Sciex API3200 (AB SCIEX, Framingham, MA, USA).

2.2. General Synthetic Procedures

Synthesis of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (2). A mixture of compound 1 (6.00 g, 20.0 mmol), 1-hydroxy benzotriazole (HOBt, 3.24 g, 24.0 mmol), and 1-ethyl-3-(3′-dimethyl aminopropyl) carbodiimide hydrochloride (EDCI, 4.60 g, 24.0 mmol) in acetonitrile (MeCN, 300 mL) was stirred at room temperature for 3 h. The mixture was then slowly added to ammonium hydroxide (NH₃·H₂O, 30 mL, 25%, v/v) at 0−10 °C and maintained at this temperature until the reaction was completed. A solvent of concentrated in vacuo and saturated aqueous sodium bicarbonate (NaHCO₃, 200 mL) was added. The mixture was extracted with ethyl acetate (EA, 3 × 100 mL). The combined organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate (Na₂SO₄), concentrated in vacuo, and purified through column chromatography to obtain product 2.

Synthesis of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbothioamide (3). A solution of compound 2 (4.50 g, 15.0 mmol) and Lawesson’s reagent (3.64 g, 9.0 mmol) in tetrahydrofuran (THF, 300 mL) was stirred at 65 °C for 2 h. After confirmation of the completion of the reaction by thin-layer chromatography (TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (EA, 200 mL), washed with saturated aqueous NaHCO₃ (100 mL × 2) and brine (200 mL), dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified through column chromatography to obtain product 3.

Synthesis of ethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (4). Ethyl bromopyruvate (2.34 g, 12.0 mmol) was dropwise added to a solution of 3 (3.16 g, 10.0 mmol) in ethanol (EtOH, 200 mL) at room temperature. Then, the solution was heated to 78 °C for 3 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with EA (200 mL), washed with saturated aqueous NaHCO₃ (2 × 100 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified through column chromatography to obtain product 4.

Synthesis of 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylic acid (5). To a solution of compound 4 (3.30 g, 8.0 mmol) in EtOH (100 mL) at room temperature, 1 mol/L NaOH (aq., 50 mL) was slowly added over 5 min. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was acidified to pH = 2 with 1 mol/L hydrochloric acid (HCl) solution. The residual aqueous solution was extracted with EA (3 × 50 mL), and the combined organic layer was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified through column chromatography to obtain product 5.

General synthesis procedures of compounds 6a−6j. A mixture of intermediate 5 (0.38 g, 1.0 mmol), dicyclohexylcarbodiimide (DCC, 0.31 g, 1.5 mmol), 4-dimethylamino pyridine (DMAP, 12 mg, 0.1 mmol), and the corresponding alcohol (1.2 mmol) in DCM (5 mL) was stirred at room temperature. When the reaction was completed according to TLC analysis, the solvent was concentrated in vacuo and purified through column chromatography to obtain product 6a−6j.

General synthesis procedures of compounds 7a−7m. Oxalyl chloride (169 μL, 2.0 mmol) was added to a mixture of intermediate 5 (0.38 g, 1.0 mmol) in DCM (3 mL), followed by a drop of dimethyl formamide at room temperature. The mixture was stirred for 2 h and evaporated to afford the crude product, which was then dissolved in DCM (2 mL). The above acyl chloride dropwise was added to an ice-cooled solution of amines (1.2 mmol) and triethylamine (TEA, 2.0 mmol) in DCM (2 mL). The solvent was removed to afford the crude product. The mixture was diluted with DCM, washed with 1 mol/L hydrochloric acid, saturated NaHCO₃, and brine, dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified through column chromatography to obtain product 7a−7m.

Synthesis of 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carbonitrile (8). Compound 7a (0.19 g, 0.5 mmol) was dissolved in DMF (2 mL), and thionyl chloride (1.0 mmol) was slowly dropped into the reaction solution at 0 °C and continuously stirred for 0.5 h. After confirmation of the completion of the reaction by TLC, water (10 mL) was added to the reaction solution and extracted with EA (3 × 5 mL). The combined organic layer was washed with water (3 × 30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified through column chromatography to obtain product 8.

2.3. Biological Materials and Methods

2.3.1. Bioassays with P. xylostella and S. exigua

P. xylostella and S. exigua were collected from the laboratory of South China Agricultural University, Guangzhou, China (23°8′ N, 113°17′ E). The insecticidal activities were evaluated based on the literature reported [8,25]. Treatment with distilled water (containing 0.1% Tween-80 and 0.01% DMSO) was used as a negative control, and chlorantraniliprole and indoxacarb were selected as a positive control. First, all the tested compounds were dissolved in DMSO (dimethyl sulfoxide) and diluted with water (containing 0.1% Tween 80). Then, the cabbage leaf disks (diameter: 1.8 cm) were dipped in the tested solution for 30 s and dried naturally. Finally, the treated cabbages leaf disks were placed in Petri dishes (diameter: 9 cm), and ten third-instar larvae of P. xylostella or second-instar of S. exigua raised in the laboratory were transferred to each petri dish. Three replicates for each treatment concentration were conducted. Mortalities (%) were determined at 48 h after treatment. SPSS 21.0 software was used for one-way analysis of variance, Duncan’s method was used for multiple comparisons, and the LC₅₀ values were calculated using Finney’s Probit analysis (Probit module in SPSS 21.0 Software). The corrected mortality (%) was obtained as follows:

Corrected mortality (%) = (mortality in treatment − mortality in negative control)/(1- mortality in negative control) × 100

2.3.2. Bioassays with S. frugiperda

S. frugiperda was collected from the laboratory of South China Agricultural University, Guangzhou, China (23°8′ N, 113°17′ E). Similarly, treatment with distilled water was used as a negative control, and indoxacarb and chlorantraniliprole were selected as a positive control. First, all tested compounds were dissolved in DMSO and diluted to 100 mg/L with distilled water (containing 0.1% Tween 80). Then, the young leaves of maize were cut into 5 cm lengths, dipped in the solution of the test compound for 10 s, and dried naturally. Finally, the treated maize leaves were placed in Petri dishes (diameter: 9 cm), and 10 s-instar larvae of S. frugiperda raised in the laboratory were placed in each petri dish [33]. Three replicates for each treatment concentration were conducted. Mortalities were determined 48 h after treatment.

3. Results and Discussion

3.1. Chemistry

The synthetic routes of the target compounds are illustrated in Scheme 1. 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid 1 was used as the starting material, and we attempted to treat 1 with ammonia in the presence of the combination of EDCI and HOBt [34] to prepare primary amide intermediate 2. Subsequently, product 3 was obtained using Lawesson’s Reagent via an oxygen-sulfur exchange reaction. Then, the thioamide product 3 and ethyl bromopyruvate through the ring-closing reaction introduced the thiazole ring into the N-pyridylpyrazole scaffold to obtain the thiazole ester compound 4 in 82% yield. Compound 4 was hydrolyzed with 1 mol/L NaOH solution, and acidified with a 1 mol/L hydrochloric acid solution to afford intermediate 5, and 71.14% overall yield for the four-step sequence.

Furthermore, the corresponding compounds 6a−6j were prepared via synthetic route A, and treated compound 5 with alcohols using DCC/DMAP as a catalyst [15]. Among them, different types of aliphatic alcohols bearing functional groups such as alkyl, alkynyl, trifluoromethyl, and trichloromethyl groups gave the corresponding products 6a−6g in good yields. In addition, this strategy was also compatible with different types of benzyl alcohol, delivering the desired products 6h and 6i in good yields. On the other hand, compound 7a−7m was prepared following another synthetic route B described in the preparation of compounds 5 with amines using a combination of oxalyl chloride/triethyl amine [35], affording the corresponding product yields of 63−98%. Interestingly, this protocol was also compatible with different types of acid amides-free N-H bonds (7g, 7i, and 7j). Finally, the primary amide compound 7a was further dehydrated to obtain the thiazole nitrile compound 8.

All synthesized compounds (6a−6j, 7a−7m, and 8) were characterized based on their ¹H NMR and ¹³C NMR spectroscopies data (see the Supporting Information for details, Figure S1–S50). In the ¹ H NMR spectra of compound 7i, a signal peak that appeared at the field of 9.47 ppm corresponded with the thiazole -CONH-Ph- proton influenced by the benzene and thiazole ring, and the pyrazole-H proton mainly appeared as a signal at 8.52 ppm. The chemical shift of the -CONH-CH₃ attached to the benzene ring is influenced by the methyl group and exhibits a quartet peak with a chemical shift at 8.50−8.47 ppm. Furthermore, in ¹³C NMR spectra compound 7i, the carbon resonance frequencies of the two C=O were at 165.61 ppm and 158.26 ppm, respectively. Finally, the -CH₃ of compound 7i appeared at 26.65 ppm; this is similar to the chemical shifts of the corresponding functional groups of chlorantraniliprole [17].

Ethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (4). White solid, yield: 82%; ¹H NMR (600 MHz, CDCl₃) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.92 (dd, J = 8.1, 1.6 Hz, 1H), 7.48 (dd, J = 8.1, 4.7 Hz, 1H), 7.04 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 160.65, 154.46, 148.30, 147.98, 147.23, 139.41, 138.58, 130.20, 128.64, 127.87, 126.36, 110.71, 61.43, 14.24. ESI-MS m/z: calcd for C₁₄H₁₁BrClN₄O₂S ([M + H]⁺), 412.94; found, 412.90.

Methyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6a). Oil, yield: 96%; ¹H NMR (600 MHz, CDCl₃) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.09 (s, 1H), 7.49 (dd, J = 8.1, 4.7 Hz, 1H), 7.05 (s, 1H), 3.86 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 161.09, 154.60, 148.16, 147.60, 147.28, 139.52, 138.61, 130.21, 128.71, 128.10, 126.41, 110.86, 52.42. ESI-MS m/z: calcd for C₁₃H₉BrClN₄O₂S ([M + H]⁺), 398.92; found, 398.90.

Prop-2-yn-1-yl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6b). White solid, yield: 96%; ¹H NMR (600 MHz, CDCl₃) δ 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (dd, J = 8.1, 4.7 Hz, 1H), 7.04 (s, 1H), 4.84 (d, J = 2.5 Hz, 2H), 2.52 (t, J = 2.5 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 159.68, 154.74, 148.24, 147.23, 146.82, 139.47, 138.38, 130.19, 128.78, 128.65, 126.48, 110.82, 77.15, 75.45, 52.75. ESI-MS m/z: calcd for C₁₅H₉BrClN₄O₂S ([M + H]⁺), 422.92; found, 422.95.

2,2,2-trifluoroethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6c). White solid, yield: 94%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.22 (s, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 7.01 (s, 1H), 4.58 (q, J = 8.3 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 158.92, 155.10, 148.35, 147.11, 145.82, 139.29, 138.00, 130.12, 129.67, 128.58, 126.40, 122.77 (q, J = 277.2 Hz), 110.81, 60.91 (q, J = 37.1 Hz). ESI-MS m/z: calcd for C₁₄H₈BrClF₃N₄O₂S ([M + H]⁺), 466.91; found, 466.90.

2,2,2-trichloroethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylat (6d). Yellow solid, yield: 97%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.26 (s, 1H), 7.92 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 7.03 (s, 1H), 4.87 (s, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 158.78, 155.19, 148.25, 147.20, 146.23, 139.49, 138.19, 130.07, 129.74, 128.67, 126.46, 111.01, 94.56, 74.49. ESI-MS m/z: calcd for C₁₄H₈BrCl4N₄O₂S ([M + H]⁺), 514.82; found, 514.85.

1,1,1,3,3,3-hexafluoropropan-2-yl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6e). White solid, yield: 93%; ¹H NMR (600 MHz, CDCl₃) δ 8.49 (dd, J = 4.7, 1.6 Hz, 1H), 8.33 (s, 1H), 7.90 (dd, J = 8.1, 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.01 (s, 1H), 5.86 (hept, J = 6.1 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 157.25, 155.53, 148.40, 147.01, 144.22, 139.19, 137.64, 131.26, 130.18, 128.58, 126.37, 120.26 (q, J = 283.3 Hz, 2C), 110.93, 66.92 (p, J = 34.9 Hz). ESI-MS m/z: calcd for C₁₅H₇BrClF₆N₄O₂S ([M + H]⁺), 534.90; found, 534.96.

Cyclopropylmethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6f). White solid, yield: 92%; ¹H NMR (600 MHz, CDCl₃) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.11 (s, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 7.04 (s, 1H), 4.08 (d, J = 7.3 Hz, 2H), 1.18 (dddd, J = 15.3, 7.5, 4.7, 2.8 Hz, 1H), 0.62−0.57 (m, 2H), 0.31 (dt, J = 6.1, 4.7 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 160.78, 154.48, 148.30, 148.05, 147.23, 139.41, 138.61, 130.21, 128.66, 127.95, 126.36, 110.76, 70.17, 9.80, 3.44 (2C). ESI-MS m/z: calcd for C₁₆H₁₃BrClN₄O₂S ([M + H]⁺), 438.96; found, 438.96.

Cyclobutylmethyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6g). White solid, yield: 91%; ¹H NMR (600 MHz, CDCl₃) δ 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 (s, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 7.02 (s, 1H), 4.21 (d, J = 6.8 Hz, 2H), 2.65 (p, J = 7.4 Hz, 1H), 2.06 (dddd, J = 12.8, 10.3, 8.2, 4.6 Hz, 2H), 1.97−1.85 (m, 2H), 1.80−1.72 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 160.83, 154.52, 148.37, 148.08, 147.18, 139.34, 138.56, 130.17, 128.65, 127.85, 126.27, 110.76, 69.09, 34.02, 24.76 (2C), 18.45. ESI-MS m/z: calcd for C₁₇H₁₅BrClN₄O₂S ([M + H]⁺), 452.97; found, 452.96.

4-(Trifluoromethyl)benzyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6h). White solid, yield: 92%; ¹H NMR (600 MHz, CDCl₃) δ 8.46 (dd, J = 4.7, 1.6 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J = 8.1, 1.6 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.1, 4.7 Hz, 1H), 7.03 (s, 1H), 5.32 (s, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 160.30, 154.78, 148.29, 147.26, 147.12, 139.39, 139.30, 138.38, 130.61 (q, J = 32.5 Hz), 130.12, 128.68, 128.64, 128.39 (2C), 126.73, 126.23, 125.54 (q, J = 3.8 Hz), 123.95 (q, J = 272.1 Hz), 110.84, 66.01. ESI-MS m/z: calcd for C₂₀H₁₂BrClF₃N₄O₂S ([M + H]⁺), 542.94; found, 542.97.

2,3,5,6-Tetrafluoro-4-(methoxymethyl)benzyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxylate (6i). White solid, yield: 95%; ¹H NMR (600 MHz, CDCl₃) δ 8.45 (dd, J = 4.7, 1.6 Hz, 1H), 8.14 (s, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (dd, J = 8.1, 4.7 Hz, 1H), 7.26 (s, 1H), 5.37 (s, 2H), 4.61 (s, 2H), 3.44 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 159.90, 154.82, 148.34, 147.07, 146.80, 145.94 (dt, J = 13.8, 4.9 Hz, 2C), 144.29 (dq, J = 14.1, 4.6, 3.9 Hz, 2C), 139.20, 138.23, 130.03, 128.87, 128.58, 126.15, 117.37 (t, J = 17.9 Hz), 114.08 (t, J = 17.0 Hz), 110.75, 61.42, 58.69, 54.29. ESI-MS m/z: calcd for C₂₁H₁₃BrClF₄N₄O₃S ([M + H]⁺), 590.94; found, 590.93.

(2-Chloropyridin-4-yl)methyl 2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole -4-carboxylate (6j). White solid, yield: 91%; ¹H NMR (600 MHz, CDCl₃) δ 8.50 (dd, J = 4.7, 1.6 Hz, 1H), 8.40 (dd, J = 5.0, 0.7 Hz, 1H), 8.21 (s, 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 7.38 (dd, J = 8.1, 4.7 Hz, 1H), 7.28−7.27 (m, 1H), 7.17 (ddt, J = 5.1, 1.5, 0.7 Hz, 1H), 7.03 (s, 1H), 5.26 (s, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 160.04, 155.02, 151.97, 149.94, 148.31, 147.73, 147.18, 146.78, 139.34, 138.25, 130.09, 129.12, 128.69, 126.28, 122.42, 120.72, 110.94, 64.18. ESI-MS m/z: calcd for C₁₈H₁₁BrCl₂N₅O₂S ([M + H]⁺), 509.91; found, 509.89.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carboxamide (7a). White solid, yield: 94%; ¹H NMR (600 MHz, DMSO-d₆) δ 8.64 (dd, J = 4.7, 1.5 Hz, 1H), 8.35−8.31 (m, 2H), 7.77 (dd, J = 8.1, 4.7 Hz, 1H), 7.71 (s, 1H), 7.47–7.42 (m, 1H), 6.84 (s, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ 161.82, 153.74, 150.89, 148.45, 147.86, 140.58, 139.04, 129.55, 128.36, 128.24, 126.73, 110.87. ESI-MS m/z: calcd for C₁₂H₈BrClN₅OS ([M + H]⁺), 383.92; found, 383.93.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-methylthiazole-4-carboxamide (7b). Yellow solid, yield: 95%; ¹H NMR (600 MHz, CDCl₃) δ 8.53 (d, J = 4.7 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.0, 4.7 Hz, 1H), 6.94 (s, 1H), 6.63 (s, 1H), 2.84 (d, J = 5.0 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 160.95, 154.05, 150.47, 148.58, 147.32, 139.33, 138.45, 130.24, 128.80, 126.22, 123.98, 110.55, 26.01. ESI-MS m/z: calcd for C₁₃H₁₀BrClN₅OS ([M + H]⁺), 396.94; found, 39.95.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-(tert-butyl)thiazole-4-carboxamide (7c). White solid, yield: 92%; ¹H NMR (600 MHz, CDCl₃) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 4.6 Hz, 1H), 6.94 (s, 1H), 6.46 (s, 1H), 1.33 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 159.48, 153.86, 151.81, 148.91, 147.19, 139.09, 138.30, 130.24, 128.78, 126.25, 123.44, 110.51, 51.26, 28.78 (3C). ESI-MS m/z: calcd for C₁₆H₁₆BrClN₅OS ([M + H]⁺), 439.99; found, 439.95.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-(2,2,2-trifluoroethyl)thiazole-4-carboxamide (7d). White solid, yield: 87%; ¹H NMR (600 MHz, CDCl₃) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.13 (s, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.49 (dd, J = 8.1, 4.7 Hz, 1H), 6.97 (s, 1H), 6.71 (t, J = 5.9 Hz, 1H), 3.95 (qd, J = 9.0, 6.6 Hz, 2H); ¹³C NMR (150 MHz, DMSO-d₆) δ 160.62, 154.09, 149.31, 148.51, 147.50, 140.72, 139.07, 129.46, 128.39, 128.37, 127.77, 124.96 (q, J = 279.1 Hz), 111.04, 39.97 (d, J = 42.0 Hz). ESI-MS m/z: calcd for C₁₄H₉BrClF₃N₅OS ([M + H]⁺), 465.93; found, 465.94.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-cyclopropylthiazole-4-carboxamide (7e). Yellow solid, yield: 92%; ¹H NMR (600 MHz, CDCl₃) δ 8.55 (dd, J = 4.7, 1.6 Hz, 1H), 8.05 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (dd, J = 8.1, 4.7 Hz, 1H), 6.95 (s, 1H), 6.57 (s, 1H), 2.78 (tq, J = 7.5, 3.8 Hz, 1H), 0.81 (t, J = 6.2 Hz, 2H), 0.48−0.42 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 161.54, 154.08, 150.28, 148.84, 147.21, 139.15, 138.21, 130.35, 128.83, 126.20, 123.96, 110.52, 22.40, 6.63 (2C). ESI-MS m/z: calcd for C₁₅H₁₂BrClN₅OS ([M + H]⁺), 423.96; found, 423.99.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide (7f). White solid, yield: 75%; ¹H NMR (600 MHz, CDCl₃) δ 8.62 (dd, J = 4.7, 1.6 Hz, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (s, 4H), 7.53 (dd, J = 8.0, 4.7 Hz, 1H), 7.02 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 158.04, 154.62, 150.14, 148.77, 147.33, 140.31, 139.33, 137.99, 130.26, 128.98, 126.45 (q, J = 3.8 Hz), 126.35 (2C), 125.46 (2C), 123.98 (q, J = 271.4 Hz), 119.14 (2C), 110.98. ESI-MS m/z: calcd for C₁₉H₁₁BrClF₃N₅OS ([M + H]⁺), 527.94; found, 527.99.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]thiazole-4-carboxamide (7g). Yellow solid, yield: 78%; ¹H NMR (600 MHz, CDCl₃) δ 9.06 (s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.14 (s, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.42 (dd, J = 8.1, 4.7 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.05 (s, 1H), 6.25 (q, J = 4.7 Hz, 1H), 2.84 (d, J = 4.9 Hz, 3H), 2.17 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 167.33, 159.18, 154.67, 150.00, 148.28, 147.37, 139.78, 138.29, 138.21, 134.13, 132.38, 132.32, 131.17, 130.11, 128.74, 126.48, 125.39, 125.19, 110.94, 26.69, 18.81. ESI-MS m/z: calcd for C₂₁H₁₆BrCl₂N₆O₂S ([M + H]⁺), 564.95; found, 564.91.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[(2-chlorothiazol-5-yl)methyl]thiazole-4-carboxamide (7h). Yellow solid, yield: 87%; ¹H NMR (600 MHz, CDCl₃) δ 8.47 (dd, J = 4.7, 1.6 Hz, 1H), 8.10 (s, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (s, 1H), 7.34 (dd, J = 8.0, 4.7 Hz, 1H), 6.96 (s, 1H), 6.91 (t, J = 5.6 Hz, 1H), 4.60 (dd, J = 6.1, 0.9 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 160.01, 154.46, 152.27, 149.61, 148.60, 147.19, 139.74, 139.15, 138.12, 137.37, 130.14, 128.84, 126.13, 124.83, 110.72, 35.61. ESI-MS m/z: calcd for C₁₆H₁₀BrCl₂N₆OS₂ ([M + H]⁺), 514.88; found, 514.89.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[2,4-dichloro-6-(methylcarbamoyl) phenyl]thiazole-4-carboxamide (7i). White solid, yield: 63%; ¹H NMR (600 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.62 (dd, J = 4.7, 1.6 Hz, 1H), 8.52 (s, 1H), 8.48 (q, J = 4.6 Hz, 1H), 8.30 (dd, J = 8.2, 1.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.1, 4.7 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 2.68 (d, J = 4.6 Hz, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 165.61, 158.26, 154.38, 149.51, 148.45, 147.65, 140.80, 138.85, 136.20, 133.10, 131.75, 131.71, 131.01, 129.33, 128.39, 128.31, 128.19, 127.48, 111.28, 26.65. ESI-MS m/z: calcd for C₂₀H₁₃BrCl₃N₆O₂S ([M + H]⁺), 584.90; found, 584.91.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]thiazole-4-carboxamide (7j). White solid, yield: 73%; ¹H NMR (600 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.60 (dt, J = 5.2, 2.6 Hz, 2H), 8.52 (s, 1H), 8.28 (dd, J = 8.2, 1.5 Hz, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.68 (dd, J = 8.2, 4.7 Hz, 1H), 7.49 (s, 1H), 2.71 (d, J = 4.6 Hz, 3H), 2.17 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 166.59, 158.08, 154.38, 149.71, 148.40, 147.61, 140.84, 138.86, 138.74, 137.34, 136.24, 132.16, 129.98, 129.32, 128.42, 128.37, 128.09, 118.62, 111.21, 108.85, 26.67, 19.02. ESI-MS m/z: calcd for C₂₂H₁₆BrClN₇O₂S ([M + H]⁺), 555.99; found, 555.95.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-(p-tolyl)thiazole-4-carboxamide (7k). White solid, yield: 81%; ¹H NMR (600 MHz, CDCl₃) δ 8.60 (dd, J = 4.7, 1.6 Hz, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.51 (dd, J = 8.1, 4.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 2.33 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 157.78, 154.28, 150.78, 148.87, 147.32, 139.25, 138.10, 134.70, 134.37, 130.28, 129.67 (2C), 128.88, 126.35, 124.66, 119.49 (2C), 110.76, 20.94. ESI-MS m/z: calcd for C₁₉H₁₄BrClN₅OS ([M + H]⁺), 473.97; found, 473.93.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-[4-(tert-butyl)phenyl]thiazole-4-carboxamide (7l). White solid, yield: 80%; ¹H NMR (600 MHz, CDCl₃) δ 8.61 (dd, J = 4.7, 1.6 Hz, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.53 (dd, J = 8.0, 4.7 Hz, 1H), 7.44−7.35 (m, 4H), 6.99 (s, 1H), 1.32 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 157.78, 154.31, 150.79, 148.91, 147.70, 147.31, 139.24, 138.06, 134.65, 130.27, 128.88, 126.37, 126.01 (2C), 124.67, 119.24 (2C), 110.76, 34.47, 31.37 (3C). ESI-MS m/z: calcd for C₂₂H₂₀BrClN₅OS ([M + H]⁺), 516.02; found, 516.01.

2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-N-mesitylthiazole-4-carboxamide (7m). White solid, yield: 78%; ¹H NMR (600 MHz, CDCl₃) δ 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.18 (s, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (s, 1H), 7.39 (dd, J = 8.0, 4.7 Hz, 1H), 6.99 (s, 1H), 6.91 (s, 2H), 2.29 (s, 3H), 2.10 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 158.52, 154.38, 150.60, 148.84, 147.24, 139.13, 138.23, 137.32, 134.97 (2C), 130.29, 130.20, 128.97 (2C), 128.86, 126.18, 124.78, 110.79, 20.96, 18.36 (2C). ESI-MS m/z: calcd for C₂₁H₁₈BrClN₅OS ([M + H]⁺), 502.00; found, 502.00.

2-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]thiazole-4-carbonitrile (8). White solid, yield: 95%; ¹H NMR (600 MHz, CDCl₃) δ 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 7.98−7.93 (m, 2H), 7.50 (dd, J = 8.1, 4.7 Hz, 1H), 7.00 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 155.95, 148.07, 147.26, 139.58, 137.30, 130.73, 129.88, 128.75, 127.74, 126.58, 113.17, 111.45. ESI-MS m/z: calcd for C₁₂H₆BrClN₅S ([M + H]⁺), 365.91; found, 365.95.

3.2. Insecticidal Activities

It is well-known that N-pyridylpyrazole derivatives possess extraordinary insecticidal activity against many insect species [12,36,37]. Hence, to screen for potential insecticide candidates, preliminary bioassays on the insecticidal activities of 25 title compounds, and positive control (indoxacarb and chlorantraniliprole) were conducted against three Lepidoptera pests (P. xylostella, S. exigua, and S. frugiperda) according to previously reported procedure [26,38]. As listed in Table 1, the preliminary screen results indicated that most of the tested compounds displayed a good insecticidal effect toward the third-instar P. xylostella larvae with mortality rates above 50% at 100 mg/L. In particular, compound 7g−7j showed mortality rates close to 100%, which is adequate for commercial insecticide indoxacarb. The LC₅₀ values of 7g−7j against the third-instar P. xylostella larvae were further determined (Table 2). Among them, compound 7g−7j exhibited good insecticidal activity, with LC₅₀ values of 5.32, 16.45, 8.96, and 10.11 mg/L, respectively. Remarkably, compound 7g displayed the highest insecticidal activity (LC₅₀ = 5.32 mg/L, 95% CI 3.95−7.18 mg/L), which was equal to that of commercial insecticide indoxacarb (LC₅₀ = 5.01 mg/L, 95 CI 3.94−6.35 mg/L).

Results also showed that the tested compounds have similar insecticidal activities against S. exigua and S. frugiperda. In short, compound 7g exhibited excellent insecticidal activity with an LC₅₀ value of 6.75 mg/L and 7.64 mg/L, which was close to that of commercial insecticide indoxacarb. Consequently, compound 7g is a potential new lead for the development of insecticides to control Lepidoptera pests.

3.3. Structure-Activity Relationship (SAR) Analysis

To assist in further exploitation of bioactive N-pyridylpyrazole thiazole derivatives, structure-activity relationship (SAR) analysis was discussed based on the results from the insecticidal experiments (Table 1 and Table 2). It was found that the effect of R² substitution on the bioactivity against P. xylostella, S. exigua, and S. frugiperda showed similar trends. In general, for thiazole esters derivatives 4 and 6a−6j, the order of R¹ group ranked according to the larvicidal activities was: -CHC≡CH (6b) > -CH₂(CF₃)₂ (6e) > -4-CF₃-PhCH₂ (6h) > -CH₂CF₃ (6c) > -Me (6a) > -2-Cl-4-pyridyl methyl (6j) > -Et (4). Compound 6b (propargyl ester) showed excellent insecticidal activity against P. xylostella (mortality rate, 80.61%) among the thiazolyl esters.

For thiazole amides and cyanide derivatives 7a−7m and 8 (100 mg/L), thiazolidine amides (7a−7d) showed weaker insecticidal activity compared to thiazole cycloalkanes, heterocyclic amides, or aryl amides (7e, and 7g−7j). For R² = phenyl amides (7f−7m), the insecticidal activities of the corresponding compounds against P. xylostella when there were electron-withdrawing groups on the benzene ring were significantly higher than those of the electron-donating groups (7f−7j > 7k−7m), and the tested compounds with electron-donating groups on the benzene ring exhibited weak insecticidal activities. On the other hand, compound 8 with thiazolyl cyanide showed moderate insecticidal activity against P. xylostella, which was weaker than that of thiazolamide compounds 7e and 7g−7h (LC₅₀ = 44.78, 5.32−16.45 mg/L, respectively). In short, compared with the insecticidal activities of compounds 7g, 7i, and 7j against P. xylostella, the compound 7g (R² = 4-Cl-2-Me-6-methylbenzamide) had relatively high bioactivity and is also worth further optimization as a potential insecticide candidate.

4. Conclusions

In conclusion, the IDM strategy could be a feasible tool for the development of pesticides. In this study, a library of novel N-pyridylpyrazole derivatives containing thiazole moiety was obtained based on highly efficient ring-closing reactions, and their insecticidal activities were investigated against insect pests (P. xylostella, S. exigua, and S. frugiperda). Bioassay results showed that these compounds exhibited good insecticidal activity against three Lepidoptera pests. In particular, compound 7g exhibited adequate insecticidal activities against P. xylostella (LC₅₀ = 5.32 mg/L), S. exigua (LC₅₀ = 6.75 mg/L), and S. frugiperda (LC₅₀ = 7.64 mg/L) compared to indoxacarb, making it a promising insecticide candidate. To the best of our knowledge, N-pyridylpyrazole containing thiazole scaffold is a novel lead to obtaining more potent analogs through structural modification and optimization.

Author Contributions

Conceptualization, S.Y. and H.X.; Data curation, J.T. and G.Y.; Funding acquisition, G.Y.; Investigation, S.Y.; Methodology, S.Y., H.P., J.T., and S.F.; Project administration, C.Z., G.Y., and H.X.; Resources H.X.; Writing-original draft, S.Y.; Writing-review & editing, C.Z. and G.Y. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figures, Scheme and Tables

Figure 1. Chemical structures of representative compounds.

Figure 2. Design strategy and structure optimization of insecticidal molecules.

Scheme 1. Synthetic route of the desired compounds.

Table 1

Insecticidal activities of the tested compounds against three Lepidoptera pests at 100 mg/L after treatment 48 h ^a.

Compd.	Mortality Rate (%)
	P. xylostella	S. exigua	S. frugiperda
4	24.24 ± 3.03 de	21.58 ± 2.52 d	0.00 ± 0.00 a
6a	43.33 ± 3.33 f	0.00 ± 0.00 a	0.00 ± 0.00 a
6b	80.61 ± 0.61 j	29.09 ± 0.91 e	60.66 ± 1.57 g
6c	51.52 ± 3.03 g	28.54 ± 2.49 e	19.95 ± 2.56 c
6d	17.50 ± 2.50 bc	0.00 ± 0.00 a	48.48 ± 1.52 f
6e	69.80 ± 1.75 i	0.00 ± 0.00 a	0.00 ± 0.00 a
6f	21.82 ± 2.78 cde	0.00 ± 0.00 a	0.00 ± 0.00 a
6g	0.00 ± 0.00 a	0.00 ± 0.00 a	28.18 ± 0.91 d
6h	68.48 ± 4.24 i	46.97 ± 1.52 g	61.87 ± 1.77 g
6i	21.21 ± 3.03 cde	62.94 ± 0.70 i	0.00 ± 0.00 a
6j	25.76 ± 2.98 e	0.00 ± 0.00 a	6.36 ± 3.19 b
7a	18.79 ± 0.61 bcd	18.18 ± 0.00 c	22.22 ± 2.78 c
7b	6.06 ± 3.03 a	10.00 ± 0.00 b	0.00 ± 0.00 a
7c	0.00 ± 0.00 a	28.18 ± 0.91 e	0.00 ± 0.00 a
7d	39.39 ± 3.03 f	0.00 ± 0.00 a	9.09 ± 0.00 a
7e	62.42 ± 1.21 h	0.00 ± 0.00 a	28.18 ± 0.91 d
7f	12.73 ± 2.73 b	58.52 ± 1.48 h	90.30 ± 0.30 h
7g	100.00 ± 0.00 l	100.00 ± 0.00 k	100.00 ± 0.00 j
7h	88.14 ± 1.86 k	38.13 ± 1.77 f	38.13 ± 1.77 e
7i	100.00 ± 0.00 l	94.44 ± 2.78 j	97.22 ± 2.78 ij
7j	100.00 ± 0.00 l	100.00 ± 0.00 k	100.00 ± 0.00 j
7k	0.00 ± 0.00 a	0.00 ± 0.00 a	0.00 ± 0.00 a
7l	0.00 ± 0.00 a	0.00 ± 0.00 a	0.00 ± 0.00 a
7m	0.00 ± 0.00 a	0.00 ± 0.00 a	0.00 ± 0.00 a
8	60.66 ± 1.57 h	16.43 ± 2.71 c	20.13 ± 1.17 c
IDC b	100.00 ± 0.00 l	100.00 ± 0.00 k	93.64 ± 3.19 hi
CHL c	100.00 ± 0.00 l	100.00 ± 0.00 k	100.00 ± 0.00 j

^a Corrected mortality rate (mean ± SE, %), SE (Standard Error), Means within a column followed by a different lowercase letter represent a significant difference (p < 0.05) ^b IDC = indoxacarb; ^c CHL = chlorantraniliprole.

Table 2

LC₅₀ values of the target compounds against three Lepidoptera pests after treatment 48 h.

Pests	Compd.	LC50 (mg/L)	95% CI (mg/L) *	Slope ± SE	χ2
P. xylostella	7g	5.32	3.95–7.18	2.10 ± 0.32	1.83
	7h	16.45	12.04–22.47	1.85 ± 0.30	2.66
	7i	8.96	6.55–12.26	1.94 ± 0.30	1.83
	7j	10.11	6.06–16.87	1.76 ± 0.34	2.65
	IDC	5.01	3.94–6.35	2.32 ± 0.33	2.40
S. exigua	7g	6.75	5.33–8.56	2.52 ± 0.34	4.82
	7i	14.42	10.61–19.61	2.07 ± 0.32	1.35
	7j	12.15	6.06–16.87	1.51 ± 0.29	2.94
	IDC	4.31	3.28–5.66	2.08 ± 0.28	0.87
S. frugiperda	7f	12.66	9.31–17.22	1.67 ± 0.28	0.93
	7g	7.64	4.84–12.05	1.97 ± 0.37	2.05
	7i	9.41	7.24–12.23	2.12 ± 0.30	2.62
	7j	8.22	6.19–10.91	1.86 ± 0.29	1.41
	IDC	11.15	9.00–13.82	2.60 ± 0.34	2.48

* LC₅₀ = lethal concentration to 50% of the population; CI = confidence interval.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/agronomy12102472/s1, Figure S1−S50. ¹H NMR and ¹³C NMR spectrum of target compounds.

References

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