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. 2022 Dec 20;8(1):709–717. doi: 10.1021/acsomega.2c05977

Design, Synthesis, and Toxicological Activities of Novel Insect Growth Regulators as Insecticidal Agents against Spodoptera littoralis (Boisd.)

Antar A Abdelhamid †,‡, Safwat A Aref §, Nabila A Ahmed §, Ahmed M M Elsaghier †, Fawy M Abd El Latif ‡,∥, Sameera N Al-Ghamdi ‡, Mohamed A Gad §,*
PMCID: PMC9835546  PMID: 36643456

Abstract

graphic file with name ao2c05977_0008.jpg

As a result of some major problems that come from using insecticides, the use of safe alternatives to these pesticides has become very necessary. Thus, a novel series of predicted toxicologically active urea, thiourea, thiosemicarbazide, oxadiazole, pyrazole, and triazine derivatives have been synthesized in a pure form to be lufenuron analogues as insect growth regulators which were screened and examined against Spodoptera littoralis (Boisd). The structure of synthesized compounds was established by means of spectroscopic and elemental analyses. Compounds b5, b2, b3, and a4 showed high insecticidal toxicity, and their LC50 values for the second larvae instar were found to be 26.63, 46.35, and 60.84 ppm, respectively, whereas the LC50 value for lufenuron as a reference insecticide was 17.01 ppm.

Introduction

Spodoptera littoralis (Boisduval, 1833) is a species of moth in the family Noctuidae;1 it is found widely in Africa, Mediterranean Europe, and Middle Eastern countries.2 It is known that the cotton leaf worm leads to great financial losses for many countries.3S. littoralis is a highly dangerous polyphosphorous moth that feeds on more than 100 species of plants of high economic value, including cotton, potatoes, corn, and vegetables.4,5 In recent years, urea and thioureas that are important sulfur- and nitrogen-containing compounds have proven to be important substances in drug research.6,7 The derivatives of urea and thioureas such as N-nitrosoureas, benzoylureas, benzoylthioureas, and diarylsulfonylureas have a wide range of activities against leukemias and solid tumors in which the most chapter of anticancer agents.8 Urea and thiourea derivatives are well-established important structures in medicinal and synthetic chemistry.9 The structural forms of this group constitute a common framework for a large variety of drugs and biologically and chemically active compounds which are used for their therapeutic and pharmacological properties.10−12 Acyl urea and acyl thiourea compounds are known for their superior activity in insecticides and plant growth-regulating activity intermediaries.13,14 In addition, heterogeneous nitrogen and sulfur are very important in the manufacture of active compounds such as herbicides and pesticides in the agrochemical industry.15 Moreover, the structure of compounds that contain an internal N–O or N–S bond can benefit plant absorption and metabolism.16,17 In continuation of our research theme, we wish to report the synthesis and characterization of new urea and thiourea derivatives which were assessed as insecticidal agents against S. littoralis instar larvae.

Materials and Methods

All prepared target compounds were estimated MP by the Fisher–John mechanical technique.

Instrumentation and Chemicals

For this study, chemicals and solvents were purchased from Sigma-Aldrich. The IR spectra of the prepared compounds were analyzed using the KBr method, and 1H NMR and 13C NMR spectra were recorded on the spectrometer model Bruker ADVANCE 400 MHz. A reference lufenuron insecticide was bought from Sigma-Aldrich. The insecticidal activity of the target synthesized compounds and lufenuron was tested against S. littoralis instar larvae.

Bioassay Screening

The insecticidal bioactivity of all prepared urea, thiourea, thiosemicarbazide, oxazole, pyrazole, and triazine derivatives was screened by standard leaf dip bioassay methods.18−25 The results of the target compounds for laboratory tests were recorded, and the concentrations required to kill 50% (LC50) of S. littoralis larvae were determined. In this article, five concentrations of urea and thiourea derivatives and 0.1% Tween-80 were used as a surfactant. Discs (9 cm diameter) of castor bean leaves were dipped in the tested concentration for 10 s, allowed to dry, and then given to the second and fourth larvae, approximately the size; the larvae were placed in glass jars (5 lb), and each treatment was repeated three times (10 larvae each). The dunked control disks in water and Tween-80 were then transferred to the untreated ones. The larvae were fed on castor beans for 48 h and then transferred to the untreated one. The mortality was calculated after 72 h at 22 ± 2 °C and 60 ± 5% relative humidity for all synthesized compounds. The mortality was calculated using Abbott’s formula.27 The measurements’ mortality relapse line was measurably dissected by probity analysis.28 The harmfulness index was determined by Sun’s equations.26

Breeding Larva Insects

S. littoralis insects were brought from fields of the agricultural research center farm at the Sohag branch during the 2020/2021 season, and the activity of the prepared compounds and lufenuron reference insecticide was tested against the S. littoralis insects.

Statistical Analysis

The mortality data of larval insects were calculated by using probit analysis via a statistical (LDP-line) equation which was used to calculate the LC50 values with 95% fiducially limits of lower and upper confidence and slope.

Results and Discussion

Synthesis

Herein, target products, namely, N-{[2-(cyanoacetyl)hydrazinyl]carbonothioyl}furan-2-carboxamide (a2), N-[(2-benzoyl-hydrazinyl)carbonothioyl]furan-2-carboxamide (a3), N-[5-(cyanomethyl)-1,3,4-oxadiazol-2-yl]furan-2-carboxamide (a4), N-(5-phenyl-1,3,4-oxadiazol-2-yl)furan-2-carboxamide (a5), 2,6-dichloro-N-{[2-(4-chlorobenzoyl) hydrazinyl]carbonothioyl}benzamide (b2), N-[(4-acetylphenyl)carbamothioyl]-2,6-dichlorobenzamide (b3), N-[(4-acetylphenyl)carbamothioyl]-4-fluorobenzamide (b4), N-{[2-(cyanoacetyl)hydrazinyl]carbonthioyl}-4-fluorobenzamide (b5), 2-(5-imino-4,5-dihydro-1H-pyrazol-3-yl)-N-phenyl hydrazinecarboxamide (c3), 2-(5-imino-1-phenyl-4,5-dihydro-1H-pyrazol3-yl)-N-phenylhydrazinecarboxamide (c4), and 1-{4-[(6-amino-1-phenyl-1,4-dihydro-1,3,5-triazin-zyl)amino]-phenyl}ethanone (c6), were successfully prepared; the obtained yield was 70–89% through the following steps.

Synthesis of Arylisothiocyanate (a1 and b1)

An equimolecular amount of acid chloride (2-furoyl chloride, 2,6-dichlorobenzoyl chloride, and 4-fluorobenzoyl chloride) was added dropwise with stirring to an equimolecular amount of ammonium thiocyanate in dry acetone and refluxed for 3 h to give a1 and b1 in a 70–89% yield.

Synthesis of N-{[2-(Cyanoacetyl)hydrazinyl]carbonothioyl}furan-2-carboxamide (a2), N-[(2-Benzoyl-hydrazinyl)carbonothioyl]furan-2-carboxamide (a3), N-[5-(Cyanomethyl)-1,3,4-oxadiazol-2-yl]furan-2-carboxamide (a4), and N-(5-Phenyl-1,3,4-oxadiazol-2-yl)furan-2-carboxamide (a5)

A solution of 2-furoyl isothiocyanate (freshly prepared in acetone as the solvent) was added to the amino derivative (cyanoacetohydrazide or benzhydrazide) in 15 mL of acetone; the reaction solution was refluxed for 3 h to produce compounds a2 and a3, respectively, which were cyclized by refluxing in acetic acid to give a4 and in triethylamine to give a5 (Scheme 1).

Scheme 1. Synthesis of Oxadiazole Derivatives a4 and a5.

Scheme 1

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Synthesis of 2,6-Dichloro-N-{[2-(4-chlorobenzoyl)hydrazinyl]carbonothioyl} Benzamide (b2), N-[(4-Acetylphenyl)carbamothioyl]-2,6-dichlorobenzamide (b3), N-[(4-Acetylphenyl)carbamothioyl]-4-fluorobenzamide (b4), and N-{[2-(Cyanoacetyl) hydrazinyl]carbonthioyl}-4-fluorobenzamide (b5)

A solution of isothiocyanate derivatives named 2,6-dichlorobenzoylisothiocyanate or 4-fluorobenzoylisothiocyanate (freshly prepared in acetone as the solvent) was added to the amino derivative (4-chlorobenzohydrazide, 1-(4-aminophenyl)ethanone, and cyanoacetohydrazide) in 15 mL of acetone, and the reaction solution was refluxed for 3 h to give b2, b3, b4, and b5 (Scheme 2).

Scheme 2. Synthesis of Thiosemicarbazide Derivatives.

Scheme 2

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Synthesis of 2-(5-Imino-4,5-dihydro-1H-pyrazol-3-yl)-N-phenyl Hydrazine-carbox-amide (c3), 2-(5-Imino-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-N-phenyl-hydrazine Carboxamide (c4), and 1-{4-[(6-Amino-1-phenyl-1,4-dihydro-1,3,5-tri-azinyl)amino]phenyl}ethanone (c6)

The reaction of phenylisocyanate with cyanoacetohydrazide in acetone afforded c2, which was then reacted with hydrazine hydrate and phenyl hydrazine to give c3 and c4, respectively. However, the reaction of phenylisocyanate with 4-aminoacetophenone gave c5, which was subsequently reacted with cyanoguanidine in a sodium ethoxide solution to give c6 (Scheme 3).

Scheme 3. Synthesis of Pyrazole and s-Triazine Derivatives.

Scheme 3

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A plausible mechanism may be suggested for the formation of the target compounds a4 and a5 as presented in the following scheme. Thus, a nucleophilic attack of the amine function of the hydrazide to the multiple carbon atoms of the isothiocyanate group afforded the carboxamide derivatives a2 and a3. Then, intramolecular nucleophilic cyclization of compounds a2 and a3 in their hydroxyl form A resulted in the formation of 1,3,4-oxadiazole via the elimination of H2S during reflux; on the other hand, in case of R=CH2CN, the nucleophilic attack of the SH group on the CN group did not take place; the analysis of the IR group confirmed the presence of the cyano group; also, 1H NMR and 13C NMR confirmed the presence of a free CH2 group (Scheme 4).

Scheme 4. Proposed Mechanism of Formation of a4 and a5.

Scheme 4

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Experimental Section

General Procedure for the Synthesis of Compounds a2–5

A mixture of an equimolecular amount of ammonium thiocyanate (50 mmol) in dry acetone and 2-furoyl chloride (50 mmol) was stirred, refluxed for 3 h (2-furoyl isothiocyanate was freshly prepared in acetone as the solvent), and then added to an amino derivative (cyanoacetohydrazide or benzhydrazide) (30 mmol) in 15 mL of acetone; the reaction mixture was then refluxed for 3 h. The precipitate was collected and washed thoroughly with H2O and crystallized from a methanol/dichloromethane mixture (1:1).29

N-{[2-(Cyanoacetyl)hydrazinyl]carbonothioyl}furan-2-carboxamide (a2)

Yellow solid (88% yield); mp 184–186 °C; IR (ν–, cm–1): 3216.09 (NH), 3107 (CHarom), 2922 (CHaliph), 2200 (CN), 1664.52 (C=O), 1580 (C=C) (Figure S1). 1H NMR (DMSO-d6), (δ ppm): 12.26 (s, 1H, NHexch), 11.50 (s, 1H, NHexch), 11.15 (s, 1H, NHexch), 8.06 (s, 1H, CHarom), 7.83 (s, 1H, CHarom), 6.75 (s, 1H, Harom), 3.85 (s, 2H, CH2aliph) (Figure S2). 13C NMR: 178.53, 160.39, 157.64, 148.75, 145.11, 118.22, 115.52, 113.07, 24.18. Anal. for C9H8N4O3S (252.249) (Figure S3). Calcd./found C:42.85/42.83, H: 3.20/3.18, and N: 22.21/22.20%.

N-[(2-Benzoylhydrazinyl)carbonothioyl]furan-2-carboxamide (a3)

Brown crystals (85% yield), mp 159–161 °C; IR (ν–, cm–1): 3206.49, 3097(CHarom), 1667.23 (C=O), 1565.44 (C=C).1H NMR (DMSO-d6), (δ ppm): 9.50 (s, 1H, NHexch), 8.50 (s, 1H, NHexch), 7.83–7.43 (m, 9H, Harom + NH), Anal. for C13H11N3O3S (289.30):Calcd/found C:53.97/53.95, H: 3.83/3.81 and N:14.52/14.50%.

N-[5-(Cyanomethyl)-1,3,4-oxadiazol-2-yl]furan-2-carboxamide (a4)

Brown powder (80% yield), mp > 300 °C. IR (ν–, cm–1): 3131 (NH), 3006 (CHarom), 2970 (CHaliph), 2200 (CN), 1660 (C=O) (Figure S4); 1H NMR (DMSO-d6), (δ, ppm): 13.17 (s, 1H, NH), 8.08 (s, 1H, CHarom), 7.75 (s, 1H, CHarom), 6.78 (s, 1H, Harom), 4.61 (s, 2H, CH2aliph) (Figure S5). 13C NMR: 184.53, 174.15, 171.15, 163.35, 147.61, 119.15, 116.36, 116.63, 113.03, 116.46 (Figure S6). Anal. for C9H6N4O3 (218.169) Calcd/found: C: 49.55/49.50, H: 2.77/2.70, and N: 25.68/25.60%.

N-(5-Phenyl-1,3,4-oxadiazol-2-yl)furan-2-carboxamide (a5)

White solid (80% yield), mp. 240–242 °C. IR (ν–, cm–1): 3102.60 (NH), 3016.63 (CHarom), 1675.55 (C=O) (Figure S7); 1H NMR (DMSO-d6), (δ, ppm): 13.10 (s, 1H, NHexch), 8.04–6.76 (m, 8H, Harom) (Figure S8). 13C NMR: 162.42, 159.27, 156.32, 148.18, 145.82, 131.07, 130.61, 129.80, 127.41, 117.92, 112.91 (Figure S9). Anal. for C13H9N3O3 (255.22) Calcd/found: C: 61.18/61.17, H: 3.55/3.54, and N: 16.46/16.45%.

General Procedure for the Synthesis of Compounds b2–5

While stirring an equimolecular of ammonium thiocyanate (50 mmol) in 20 mL of dry acetone, an acid chloride named 2,6-dichlorobenzoyl chloride or 4-fluorobenzoyl chloride in 15 mL of acetone (50 mmol) was added dropwise and refluxed for 3 h at 200 °C. The amino derivative [4-chlorobenzohydrazide, 1-(4-aminophenyl)ethanone, and cyanoacetohydrazide)] (30 mmol) in 15 mL of acetone was added to the mixture, and then the reaction mixture was refluxed for 3 h. The precipitate was collected and washed thoroughly with H2O and crystallized from a methanol/dichloromethane mixture (1:1).

2,6-Dichloro-N-{[2-(4-chlorobenzoyl)hydrazinyl]carbonothioyl}benzamide (b2)

Yellow solid (80% yield) mp > 300 °C; IR (ν–, cm–1): 3151 (NH), 3008.30 (CHarom), 1688.97(C=O), 1607.50 (C=C). 1H NMR (DMSO-d6), (δ ppm): 11.89 (s, 1H, NHexch), 11.24 (s, 1H, NHexch), 9.90 (s, 1H, NHexch), 7.36–8.80 (m, 7H, Harom) (Figure S11). 13C NMR: 181.34, 169.71, 168.64, 163.73, 152.34, 151.34, 131.43, 130.39, 128.92, 128.62, 116.64, 115.64 (Figure S8). Anal. for C15H10Cl3N3O2S (402.68): Calcd./found: C:44.74/44.73,H: 2.50/2.49 and N:10.44/10.43%.

N-[(4-Acetylphenyl)carbamothioyl]-2,6-dichlorobenzamide (b3)

Brown solid (85% yield), mp 140–141 °C; IR (ν–, cm–1): 3312.57 (NH), 3210.44 (NH), 3060.99 (CHarom), 1667.21 (C= O). 1H NMR (DMSO-d6), (δ ppm): 12.41 (s, 1H, NHexch), 11.13 (s, 1H, NHexch), 7.58–8.01 (s, 7H, Harom), 2.61 (s, 3H, CH3) (Figure S12). 13C NMR: 194.13, 181.12, 156.13, 163.73, 154.56, 149.12, 142.56, 139.14, 131.49, 126.13, 124.16, 115.24, 31.12 (Figure S13). Anal. for C16H12Cl2N2O2S (367.24): Calcd./found: C, 52.33/52.30, H:3.92/3.90, and N:7.63/7.61%.

N-[(4-Acetylphenyl)carbamothioyl]-4-fluorobenzamide (b4)

White powder (76% yield), mp 200–201 °C. IR (ν–, cm–1): 3473–3102 (NH), 3060 (CHarom), 1676 (C=O) (Figure S14); 1H NMR (DMSO-d6), (δ, ppm): 12.67 (s, 1H, NH), 11.76 (s, 1H, NH), 7.34–8.08 (m, 8H, Harom), 2.56 (s, 3H, CH3) (Figure S15). 13C NMR: 197.30, 173.44, 169.34, 166.34 166.30, 164.13, 142.62, 136.71, 135.11, 134.11, 130.12, 118.11, 116.64, 29.14 (Figure S16). Anal. for C16H13FN2O2S (3.16.35) Calcd/found: C: 60.75/60.72, H: 4.14/4.11, and N: 8.86/8.85%.

N-{[2-(Cyanoacetyl)hydrazinyl]carbonothioyl}-4-fluorobenzamide (b5)

Yellow powder (80% yield), mp 195–196 °C. IR (ν–, cm–1): 3300–3216 (3NH), 3051 (CHarom), 2937 (CHaliph), 2200 (CN), 1679 (C=O) (Figure S17); 1H NMR (DMSO-d6), (δ, ppm): 12.82 (s, 1H, NH), 12.64 (s, 1H, NH), 11.29 (s, 1, NH), 8.07–7.34 (m, 4H, Harom), 3.96 (s, 2H, CH2aliph) (Figure S18). 13C NMR: 180.12, 169.37, 161.13, 158.50, 151.80, 136.12, 132.30, 113.14, 23.64 (Figure S19): Anal. for C11H9FN4O2S (280.27) Calcd/found: C: 47.14/47.10, H: 3.24/3.20 and N: 19.99/19.89%.

General Procedure for the Synthesis of Compounds c2–5

An equimolecular amount (5 mmol) of cyanoacetohydrazide or 4-aminoacetophenone in 15 mL of acetone and phenylisocyanate (c1) (5 mmol) was added and refluxed for 3 h. The precipitate was collected and washed thoroughly with H2O and crystallized from a methanol/dichloromethane mixture (1:1) to produce c2 and c5, respectively.

An equimolecular amount (5 mmol) of compound c2 in ethanol (15 mL) was added to an appropriate reagent, namely, hydrazine or phenylhydrazine, and the reaction mixture was refluxed for 5 h. The precipitate was collected by filtration, washed thoroughly with H2O, dried, and purified by crystallization from ethanol to produce c4 and c3, respectively. On the other hand, a suspension of compound c2 (10 mmol) in chloroform (20 mL) and cyanoguanidine (3 mmol) was added. The reaction mixture was refluxed for 3 h and cooled to room temperature, and the precipitate was collected by filtration, washed thoroughly with H2O, dried, and purified by crystallization from ethanol to give compound c6.

2-[Cyanoacetyl]-N-phenylhydrazine-2-carboxamide (c2)

White solid crystal yield (89%); mp 160–161 °C; IR (ν–, cm–1): 3329.71 (NH), 3307.28 (NH), 3210.63 (NH), 3017.88 (CHarom), 2958.63 (CHaliph), 2200 (CN), 1708.18 (C=O), 1661.81 (C=O), 1608.45 (C=C) (Figure S20). 1H NMR (DMSO-d6), (δ ppm): 10.00 (s, 1H, NHexch), 8.70 (s, 1H, NHexch), 8.20 (s,1H, NH), 7.45–6.98 (m, 4H, Harom), 3.72 (s, 2H, CH2alpht) (Figure S21). 13C NMR: 162.62, 155.39, 129.08, 122.29, 119.28, 116.06, 26.37 (Figure S22). Anal. for C10H10N4O2 (218.212): Calcd/found; C: 55.04/55.02, H: 4.62/4.61, and N: 25.68/25.66%.

2-(5-Imino-4,5-dihydro-1H-pyrazol-3-yl)-N-phenylhydrazinecarboxamide (c3)

Brown solid (80% yield), mp 140–141 °C. IR (ν–, cm–1): 3408.59 (NH), 3261.51 (NH), 3031.43 (CHarom), 1647.78 (C=O), 1592.53 (C=C) (Figure S23); 1H NMR (DMSO-d6), (δ, ppm): 9.71 (s, 1H, NHexch), 8.64 (s, 1H, NHexch), 8.60 (s, 1H, NHexch), 7.51–6.91 (m, 5H, CHarom + 2NH), 4.36(s, 2H, CH2aliph) (Figure S24). 13C NMR: 157.82, 142.82, 140.37, 140.15, 133.44, 129.23, 129.01, 122.31, 121.85, 118.71, 118.61, 39.60 (Figure S25). Anal. for C10H12N6O (232.24) Calcd/found: C: 51.72/51.71, H: 5.21/5.19, and N: 36.19/36.18%.

2-(5-Imino-1-phenyl-4,5-dihydro-1H-pyrazol3-yl)-N-phenylhydrazinecarboxamide (c4)

Red solid (70% yield); mp. 190–192 °C. IR (ν–, cm–1): 3449.60 (NH), 3330 (NH), 3212.22 (NH), 3022.5 (CHarom), 1659.42 (C=O), 1592.53 (C=C). 1H NMR (DMSO-d6), (δ ppm): 10.03 (s, 1H, NH), 8.76 (s, 1H, NH), 8.64–6.98 (m, 10H, CHarom), 6.81 (s, 1H, NH), 3.73 (s, 2H, CH2aliph), 3.35 (s, 1H, NHach), 13C NMR: 163.05(C=O), 157.04 (C–NH), other aromatic C–H carbons at 156.52, 155.46, 154.07, 149.78, 140.09, 139.78, 138.53, 134.05, 130.76, 130.17, 129.94, 129.51, 129.24, 129.11, 128.97, 124.66, 124.32, 123.60, 122.68, 122.34, 121.43, 120.05, 119.56, 119.31, 118.99, 118.75, 116.08, 113.01, 24.36 (CH2aliph). Anal. for C16H16N6O (308.337) Calcd/found: C:62.32/62.3, H:5.23/5.19, and N:27.26/27.56%.

1-(4-Acetylphenyl)-3-phenylurea (c5)

Yellow solid (86% Yield) mp. 180–182 °C; IR (ν–, cm–1): 3341.80 (NH), 3304.45 (NH), 3040.48 (CHarom), 1740.28 (C=O), 1655.54 (C=O).1H NMR (DMSO-d6), (δ ppm): 9.04 (s, 1H, NH), 8.74 (s, 1H, NHexch), 7.92–7.01 (m, 9H, Harom), 2.52 (s, 3H, CH3) (Figure S26). 13C NMR: 197.85, 152.82, 144.66, 139.31, 130.96, 130.13, 129.33, 123.11, 119.28, 117.87, 26.63 (Figure S27). Anal. For C15H14N2O2 (254.28): Calcd./found C: 70.85/70.84, H: 5.55/5.53, and N: 11.02/11.01%.

1-{4-[(6-Amino-1-phenyl-1,4-dihydro-1,3,5-triazinyl)amino]-phenyl}ethanone (c6)

Brown crystal (80% yield), mp 209–210 °C. IR (ν–, cm–1): 3476.77, 3386.62 (NH2, NH), 3243.09 (NH), 3188.03 (NH), 3005.83 (CHarom), 2898.16 (CHaliph), 1610.19(C=O), 1596.98 (C=C) (Figure S28); 1H NMR (DMSO-d6), (δ, ppm): 9.12 (s, 2H, 2NH), 7.89–6.97 (m, 9H, Harom + s, 3H, NH), 2.51 (s, 3H, CH3aliph) (Figure S29). 13C NMR: 196.70, 152.81, 145.04, 139.94, 130.83, 130.03, 129.21, 122.57, 118.97, 117.64, 26.72 (Figure S30). Anal. For C17H16N6O (320.34) Calcd/found: C: 63.74/63.73, H: 5.03/5.02, and N: 26.23/26.21%.

Compounds a2–5, b2–5, c3, c4, and c6 were tested against the second larval insect. As shown in Table 1, the bioefficacy results of tested compounds exhibit high to low toxicological activity against the second larvae, for which the LC50 values vary from 26.63 to 313.11 ppm; for example, the LC50 values of compounds a2–5, b2–5, c3, c4, and c6 were 97.01, 114.10, 73.35, 186.48, 46.35, 60.84, 86.93, 26.63, 128.41, 145.56, and 313.11 ppm, respectively, and that of the lufenuron standard insecticide value was 17.01 ppm. Thus, the toxicity of synthesized compound b5 against the second larva instar insect was close to the insecticidal bioactivity of reference lufenuron.

Table 1. Insecticidal Activity of Compounds a2–5, b2–5, c3, c4, c6, and Lufenuron as the Reference Insecticide against the Second and Fourth Larva Instar of S. littoralis after 72 h of Treatment.

Second instar larvae
 4th instar larvae
comp. LC50 (ppm) slope toxic ratioa LC50 (ppm) slope toxic ratioa
Lufenuron 17.01 0.246 ± 0.0791 1 103.12 0.234 ± 0.083 1
a2 97.37 0.229 ± 0.0813 0.174 798.35 0.418 ± 0.953 0.129
a3 114.10 0.307 ± 0.0993 0.147 881.36 0.853 ± 0.287 0.117
a4 73.35 0.460 ± 0.0805 0.231 793.35 0.418 ± 0.953 0.129
a5 186.48 1.365 ± 0.388 0.279 965.18 2.083 ± 1.0779 0.106
b2 46.35 1.295 ± 0.3923 0.366 148.56 0.302 ± 0.0953 0.694
b3 60.84 0.225 ± 0.8201 0.279 152.06 0.239 ± 0.0985 0.677
b4 86.93 0.231 ± 0.0823 0.196 745.39 3.176 ± 1.184 0.137
b5 26.63 0.246 ± 0.0805 0.638 145.90 0.307 ± 0.0993 0.706
c3 128.41 0.2971 ± 0.0978 0.133 254.41 0.225 ± 0.0820 0.405
c4 145.56 0.307 ± 0.0993 0.116 1253.1 0.422 ± 0.938 0.082
c6 313.11 1.815 ± 1.0141 0.0543 1588.3 0.4.36 ± 1180 0.064
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a

Notes: toxicity ratio is calculated as lufenuron’s LC50 value for baseline toxicity/the compounds’ LC50 value. Toxicological activity test for the second larvae.

Table 1 shows the result of toxicity for the synthesized compounds a2–5, b2–5, c3, c4, and c6. After 72 h of treatment, high to low toxicological activity against the fourth larvae was observed, for which the LC50 values vary from 145.90 to 1588.36 ppm; for example, the LC50 values of compounds a2–5, b2–5, c3, c4, and c6 were 798.35, 881.36, 793.35, 965.18, 148.56, 152.06, 745.39, 145.90, 254.41, 1253.1, and 1588.3 ppm, respectively. The results obtained for compounds a2–5, b2–5, c3, c4, and c6 showed that b5 > b2 > b3 > a4 > b4 > a2 > c3 > a3 > a5 > c4 > c6, for which the lufenuron value was 103.12 ppm. For this result, the toxicity of compound b5 and b2 against 4th larvae was nearly lufenuron after 72 h. The LC50 value of compounds b5 and b2 was 145.90 and 148.56 ppm, respectively, and that of lufenuron was 103.12 ppm.

Structure–Activity Relationship

According to the toxicity values in Table 1 and Figure 1, by using a computerized regression analysis program, the median lethal concentration (LC50) and slope values of the target compounds were computed and reported as parts per million (ppm). The insecticidal activity of the synthesized compounds (a2–5, b2–5, c3, c4, and c6) was compared with that of lufenuron against S. littoralis, for which the second instar larvae are represented by black lines and the fourth instar larvae are represented by red lines after 72 h of treatment (Figures 2 and S32). The structure–activity relationship was established. The benzamide compound b5 is more active against the second and fourth larval insects than the other benzamide-synthesized derivatives. The high activity of compound b5 may be due to the presence of fluorophenyl and cyano in its structure. The presence of fluorophenyl and cyano moieties in this compound which is considered as an electron-withdrawing group increases the activity of the other urea and/or thiourea-synthesized derivatives compared to the commercial lufenuron insecticide. On the other hand, compound b4 exhibited good activity, which might be due to the presence of the fluorophenyl moiety in its structure. Also, the toxicity of compound b2 was higher, which might be due to the presence of a dichlorophenyl group in its structure. The aromatic moiety also enhanced the insecticidal activity. The b5 compound is higher in toxicity than compounds b2, b3, and a4, and this is due to the presence of fluorophenyl and cyano groups in its structure.

Figure 1.

Figure 1

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Insecticidal activity of compounds a2–5, b2–5, c3, c4, and c6 against the second and fourth larva instar of S. littoralis (Boisd.) after 72 h of treatment compared to lufenuron as the standard insecticide. Toxicological activity test for adult fourth larvae.

Figure 2.

Figure 2

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Insecticidal activities of selective compounds a2–5, b2–5, c3, c4, c6, and lufenuron as the reference insecticide for the second and fourth larval instar of S. littoralis after treatment.

Conclusions

A new series of urea, thiourea, thiosemicarbazide, pyrazole, oxadiazole, and triazine derivatives have been prepared in a good yield via the reaction of an acid chloride and an equimolar amount of ammonium thiocyanate in dry acetone and amine derivatives, and their chemical structure was established based on spectral and elemental data. The synthesized compounds are analogous to insect growth-regulating insecticides. The activity of these new compounds was tested against the second and fourth larval insects, and they showed good toxicological activities. It has been found that the compound b5 has an activity close to that of the standard reference lufenuron, whose LC50 was found to be 26.63 ppm, whereas the LC50 for lufenuron was 17.01 ppm, which might be due to the presence of a fluorine atom and a cyano group in its structure. In the structure–activity relationship studies, the synthesized compounds that contain a halogen in their structure play a principal role in the activity..

Acknowledgments

The authors gratefully acknowledge the Research Institute of Plant Protection, Agriculture Research Center, 12112 Giza, Egypt, and Faculty of Science, Sohag University, Egypt, for the facility and support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c05977.

  • IR spectra, 1H NMR spectra, 13C NMR spectra, and elemental analysis of urea, thiourea, thiosemicarbazide, oxadiazole, pyrazole, and triazine derivatives (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c05977_si_001.pdf (1.5MB, pdf)

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Supplementary Materials

ao2c05977_si_001.pdf (1.5MB, pdf)

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