Synthesis, SAR studies, and insecticidal activities of certain N-heterocycles derived from 3-((2-chloroquinolin-3-yl)methylene)-5-phenylfuran-2(3H)-one against Culex pipiens L. larvae

Abstract

An acid hydrazide derivative was synthesized and transformed into a variety of valuable N-heterocycles such as pyridazinone, oxadiazole, triazolopyridazinone, and triazole derivatives via reactions with certain carbon electrophiles such as 4-methoxybenzaldehyde, indole-3-carbaldehyde, pentan-2,4-dione, and carbon disulfide. The chemical structures of all prepared compounds were verified via their analytical and spectroscopic data. The insecticidal activity of the N-heterocycles was evaluated against field and lab strains of the third larval instar of Culex pipiens. All tested compounds exhibited higher larvicidal activity against the lab strains compared to the field strains, with dissimilar ratios. The obtained results demonstrate that the high toxicity achieved by oxadiazole followed the order of furanone, pyridazinone and hydrazide, with lower LC₅₀ values of the hydrazone and N-acetylpyridazinone derivatives compared to that of imidacloprid. Interestingly, these compounds are promising agents for insect pest control, especially since they are insoluble in water and can overcome the disadvantages of neonicotinoid applications in pest management programs.

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Introduction

Heterocyclic compounds, especially nitrogen heterocycles, play an important role in the process of drug development and drug analysis (approximately two-thirds of the medicines available on the market include a heterocyclic skeleton).^1–13 Accordingly, furanones are found to be easily converted to a variety of heterocyclic skeletons of biological importance.^14–20 A broad range of pharmacological activities including insecticidal, antiviral, anticancer, antimicrobial, antimalarial, anti-inflammatory, and analgesic properties have been documented in quinoline (benzo[b]pyridine) derivatives (Fig. 1). The quinoline skeleton has been utilized for certain important engineered agrochemicals and to plan manufactured mixtures possessing many pharmacological effects.^21–28

Fig. 1 Some quinoline-based drugs.

Mosquitoes are the main vector of serious diseases that threaten human health and cause adverse socioeconomic impacts, particularly in subtropical and tropical climates.^29,30 Culex pipiens Linnaeus (Diptera: Culicidae) is a widely distributed and epidemic mosquito found in Egypt.³¹ It is the vector of the West Nile virus, Rift Valley fever virus, and filariasis.^32,33 Synthetic chemicals are a major, rapid, and effective control measure for mosquitoes, especially at the outbreak of diseases.³⁴ However, the injudicious and intensive use of chemical insecticides for vector control is common malpractice, especially in developing countries.³⁵ The accumulation of insecticide residues and the development of resistance in the target insect have adverse impacts on public health, ecological balance, and the environment, which gradually leads to the failure of the commercial products.^36,37

Meanwhile, the widespread nature of mosquito breeding sites makes the application of insecticides for mosquito control inevitable.³⁸ Consequently, the creation and evaluation of the toxicity of novel chemicals are important to develop new control recommendations. Neonicotinoids with a pyridine moiety have high efficacy against insects as well as distinctive characteristics such as a specific and selective mode of action for insect nicotinic acetylcholine receptors (nAChRs), thus exhibiting low mammalian toxicity in addition to a lack of cross-resistance with other insecticide groups and systemic properties.^39–41 Even so, these systemic insecticides (soluble in water) may affect pollinators due to the accumulation of their traces in the plant nectar and pollen.⁵⁴ Neonicotinoids possess molecular characteristics such as an aromatic heterocycle, hydroheterocycle, guanidine/amidine, flexible linkage, and electron-withdrawing segment.⁴² Thus, it is crucial to discover new hydrophobic heterocycles related to neonicotinoids with desired toxicological potencies to overcome this problem, target different insect pests and offer new methods of applications. The present study aims to synthesize and assess the activity of a few new N-heterocycles based on the benzopyridine group against lab and field strains of C. pipiens larvae.

Results and discussion

Synthesis

The requisite acid hydrazide derivative 2, obtained via hydrazinolysis of the corresponding furan-2(3H)-one derivative 1,⁴³ was reacted with a few different carbon electrophiles to form a variety of valuable heterocycles including oxadiazole, triazole, and pyridazinone derivatives. First, its treatment with aromatic or heterocyclic aldehydes such as 4-methoxybenzaldehyde and indole-3-carbaldehyde in refluxing dioxane yielded the corresponding hydrazone derivatives 3 and 4 (Scheme 1). Alternatively, reacting 2 with pentan-2,4-dione in boiling dioxane achieved the pyridazinone derivative 5, which was confirmed by characterization.⁴³ Second, the interaction of 2 with acetic anhydride under reflux conditions afforded the N-acetylpyridazinone derivative 6 (Scheme 1). The IR spectra of compounds 3, 4, and 6 exhibit NH and C=O absorption bands. The ¹H NMR spectra of 3 and 4 reveal a singlet signal for the methine proton of the CH=N group at δ 9.34 and 9.45 ppm, respectively, as well as a singlet signal for the methyl protons of the OCH₃ group at δ 3.81 ppm for compound 3 and an exchangeable singlet signal for the NH of the indole ring at δ 11.95 ppm for compound 4. The ¹H NMR spectrum of 6 showed an exchangeable singlet signal for NH at δ 12.09 ppm as well as signals for the =CH of the pyridazinone ring at δ 7.13 ppm and methyl protons at δ 2.36 ppm. Their ¹³C NMR spectra provided additional evidence for the assigned structures. Further, the mass spectra of 3 and 6 exhibited their correct molecular ion and M + 2 peaks, as well as other important fragments (Experimental section).

Scheme 1 Reactions of the hydrazide 2 with certain carbonyl compounds.

Third, the action of hydrazide 2 with carbon disulfide was investigated and studied under various conditions. The 5-mercapto-1,3,4-oxadiazole derivative 7 was produced by refluxing 2 in an ethanolic solution containing sodium hydroxide and carbon disulfide. Similarly, stirring the latter reaction mixture in ethanol with potassium hydroxide at room temperature yielded the corresponding potassium dithiocarbazinate 8, which was then treated with hydrazine hydrate in refluxing water or ethanol to construct the triazolopyridazine derivative 9 and 4-amino-5-mercapto-1,2,4-triazole derivative 10, respectively (Scheme 2).

Scheme 2 Reactions of the hydrazide 2 with carbon disulfide under different conditions.

The IR spectra of compounds 7 and 9 show the absorption bands for the NH and CO moieties. Their ¹H NMR spectra reveal two exchangeable broad singlet signals for NH and SH at δ 11.85; 13.20 and 11.81; 13.15 ppm for 7 and 9, respectively, as well as the signal for the methylene group. Further support for the proposed structure 7 was obtained from its ¹³C NMR and EIMS spectra (Experimental section). The amino and carbonyl groups were found in the IR spectrum of 10. Its ¹H NMR spectrum indicated its existence as a mixture of two tautomeric forms: thiolactam and thiolactim in a ratio of 1 : 3 (Experimental section). Because of the stability of the aromatic triazole ring, the thiolactim form has a greater abundance. Furthermore, its mass spectrum showed the correct M⁺ peak at m/z 422 (33.43%) as well as the M + 2 peak at m/z 424 (17.89%), indicating the existence of the chlorine isotope.

Insecticidal activity

The results of the larvicidal activity of the synthesized compounds and imidacloprid (IMI) exhibited good mortality against the third larval instar of lab and field strains of C. pipiens, indicating that the tested compounds can significantly control C. pipiens at the larval stage. Additionally, the tested compounds were more effective against the lab strain than the field population of C. pipiens larvae, as seen in Tables 1–4, with resistance ratios of 9.12, 11.06, 9.44, 13.14, 10.12, 9.49, and 8.62 for the compounds 1, 2, 3, 5, 6, 7 and IMI, respectively, at 48 h post-treatment (Table 2). Abou Rawash, Giza, where the field strain was collected, is a rural area, and many agricultural and public health insecticides are applied there. Thus, tolerance or reduction in the sensitivity of the field strain of C. pipiens larvae might be due to past insecticide application conferring cross-resistance as well as natural variations.⁴⁴ The selection pressure of imidacloprid against Ae. aegypti larvae in the laboratory for several generations cause over-transcription of multiple genes encoding cuticle proteins, which reduce the penetration of the insecticide molecules through the insect cuticle.⁴⁵ The mosquito could be affected by agricultural practices, pesticides used in agriculture and natural xenobiotics present in mosquito breeding sites, which confer cross-resistance to multiple insecticides.⁴⁶

Table 1 Toxicity of the tested compounds against the field strain of the third instar of Culex pipiens larvae after 24 h^a

a (F.l.) fiducial limits. Slope of the concentration–inhibition regression line ± standard error. (χ^2) chi square value. (RR) resistance ratio.
Compounds (μg ml^−1)	1	2	3	5	6	7	IMI
LC25 (F.l. at 95%)^a	4.52 (1.52–8.014)	12.08 (7.29–16.89)	9.18 (1.8–16.78)	7.69 (5.25–10.18)	12.40 (5.77–19.19)	6.51 (3.44–9.72)	6.31 (3.16–9.64)
LC50 (F.l. at 95%)^a	18.58 (11.46–27.06)	33.69 (25.21–45.49)	38.87 (23.87–61.84)	22.73 (17.83–29.66)	53.19 (35.97–93.42)	18.52 (13.06–24.77)	19.07 (13.24–25.84)
LC90 (F.l. at 95%)^a	272.11 (136.42–1063.46)	236.31 (141.77–561.1)	603.21 (228.24–10 439.6)	177.91 (109.88–374.54)	845.92 (322.59–6822.22)	134.84 (86.457–278.31)	155.69 (95.97–351.45)
Slope ± SE^a	1.09 ± 0.15	1.51 ± 0.16	1.07 ± 0.21	1.43 ± 0.13	1.06 ± 0.15	1.48 ± 0.16	1.405 ± 0.15
P	0.13	0.909	0.373	0.237	0.641	0.835	0.995
χ^2^a	7.105	1.001	3.11	5.53	2.51	1.44	2.206
Toxicity index	99.67	54.97	47.64	81.47	34.81	100	97.11
Relative potency	2.86	1.57	1.36	2.34	1	2.87	2.79
RR	7.74	10.43	9.74	8.26	14.26	9.9	9.5

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Table 2 Toxicity of the tested compounds against the field strain of the third instar of Culex pipiens larvae after 48 h

a (F.l.) fiducial limits. Slope of the concentration–inhibition regression line ± standard error. (χ^2) chi square value.
Compounds (μg ml^−1)	1	2	3	5	6	7	IMI
LC25 (F.l. at 95%)^a	2.94 (1.05–5.22)	5.8 (2.83–8.96)	4.64 (1.44–8.39)	4.99 (2.47–7.68)	6.94 (2.86–11.33)	2.24 (0.64–4.29)	2.59 (0.81–4.82)
LC50 (F.l. at 95%)^a	9.67 (5.54–13.99)	17.59 (12.04–23.9)	20.59 (12.64–30.59)	14.07 (9.53–19.01)	27.408 (18.43–40.14)	7.69 (3.91–11.62)	9.05 (4.88–13.41)
LC90 (F.l. at 95%)^a	92.49 (58.43–202.47)	144.73 (89.85–322.29)	348.94 (161.64–1711.96)	101.04 (66.74–196.39)	371.89 (178.57–1579.12)	79.74 (49.23–188.9)	97.19 (59.87–227.82)
Slope ± SE^a	1.307 ± 0.16	1.4 ± 0.15	1.042 ± 0.15	1.4973 ± 0.1635	1.13 ± 0.15	1.26 ± 0.17	1.24 ± 0.16
P	0.0695	0.37	0.149	0.0509	0.45	0.918	0.89
χ^2^a	8.68	4.27	6.7547	9.4461	3.68	5.945	1.108
Toxicity index	79.52	43.71	37.34	54.65	28.05	100	84.97
Relative potency	2.83	1.55	1.33	1.94	1	3.56	3.03
RR^a	9.12	11.06	9.44	13.14	10.12	9.49	8.62

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Table 3 Toxicity of the tested compounds against the lab strain of the third instar of Culex pipiens larvae after 24 h

a (F.l.) fiducial limits. Slope of the concentration–inhibition regression line ± standard error. (χ^2) chi square value.
Compounds (μg ml^−1)	1	2	3	5	6	7	IMI
LC25 (F.l. at 95%)^a	0.76 (0.38–1.15)	1.1 (0.63–1.57)	1.05 (0.502–1.62)	0.94 (0.53–1.36)	1.07 (0.55–1.59)	0.55 (0.24–0.89)	0.52 (0.205–0.88)
LC50 (F.l. at 95%)^a	2.4 (1.69–3.28)	3.23 (2.38–4.41)	4.101 (2.85–6.37)	2.75 (2.014–3.706)	3.73 (2.65–5.47)	1.87 (1.25–2.6)	2.003 (1.29–2.86)
LC90 (F.l. at 95%)^a	21.29 (12.36–54.99)	25.05 (14.58–63.73)	54.003 (24.05–275.25)	20.74 (12.51–48.808)	40.01 (19.91–150.26)	18.63 (10.77–49.25)	25.16 (13.21–85.38)
Slope ± SE^a	1.35 ± 0.15	1.44 ± 0.16	1.14 ± 0.15	1.46 ± 0.16	1.24 ± 0.15	1.28 ± 0.15	1.16 ± 0.15
P	0.49	0.66	0.701	0.23	0.67	0.81	0.93
χ^2^a	3.41	2.409	2.18	5.502	2.34	1.58	2.92
Toxicity index	77.91	57.89	45.59	68	50.13	100	93.35
Relative potency	1.7	1.27	1	1.5	1.01	2.19	2.04

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Table 4 Toxicity of the tested compounds against the lab strain of the third instar of Culex pipiens larvae after 48 h

a (F.l.) fiducial limits. Slope of the concentration–inhibition regression line ± standard error. (χ^2) chi square value.
Compounds (μg ml^−1)	1	2	3	5	6	7	IMI
LC25 (F.l. at 95%)^a	0.3 (0.099–0.54)	0.52 (0.25–0.82)	0.57 (0.22–0.95)	0.37 (0.16–0.603)	0.74 (0.33–1.17)	0.24 (0.079–0.45)	0.31 (0.11–0.55)
LC50 (F.l. at 95%)^a	1.06 (0.601–1.55)	1.59 (1.07–2.17)	2.18 (1.43–3.14)	1.07 (0.67–1.48)	2.707 (1.86–3.87)	0.81 (0.43–1.204)	1.05 (0.61–1.52)
LC90 (F.l. at 95%)^a	11.75 (7.05–29.18)	13.07 (8.21–28.42)	28.09 (14.407–101.06)	7.95 (5.31–15.16)	31.304 (16.09–109.78)	7.88 (5.038–16.91)	10.69 (6.59–24.78)
Slope ± SE^a	1.22 ± 0.15	1.401 ± 0.15	1.15 ± 0.15	1.47 ± 0.16	1.205 ± 0.15	1.29 ± 0.16	1.27 ± 0.15
P	0.34	0.8459	0.38	0.28	0.56	0.28	0.53
χ^2^a	4.46	1.39	4.14	5.06	2.98	5.003	3.13
Toxicity index	76.41	50.94	37.15	75.7	29.92	100	77.14
Relative potency	2.55	1.7	1.24	2.53	1	3.34	2.57

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The larval mortality showed a concentration and time-dependent behavior, as larval mortality increased with increasing concentration of the tested compounds and time of exposure. The obtained results showed that different levels of mortality were achieved by different tested compounds for both the susceptible and field strains, as shown in Fig. 2–5. For the field strain, great variation in the susceptibility of C. pipiens larvae towards the tested compounds was observed, whereas 7, 1, and IMI showed high activity with toxicity indexes of 100%, 99.67%, and 97.11% 24 h post-treatment (Table 1). The toxicities of 1, IMI, and 7 are about 3, 3, and 4 times that of 6, respectively, after 48 h with low LC₅₀ values of 7.69, 9.05, and 9.67 μg mL⁻¹, respectively (Table 2). For the lab strain, the toxicity indexes of 1, 2, 3, 5, 6, and IMI were 77.91%, 57.89%, 45.59%, 68%, 50.13%, and 93.35%, respectively, compared to 7, which showed 100% after 24 h of treatment (Table 3). At 48 h post-treatment, the toxicity of most tested compounds was convergent; however, 1, 5, 7, and IMI displayed high potencies 2.55, 2.53, 3.34, and 2.57 times that of 6, respectively, with LC₅₀ values of 0.81, 1.06, 1.07 and 1.05 μg mL⁻¹, respectively (Table 4). The chi-square values were significant at P < 0.01. The low slope values of all treatments revealed the homogeneity of the tested populations. In conclusion, the obtained results demonstrate that the high toxicities achieved by 7 followed by 1 then 5 make them promising agents for the control of insect pests.

Fig. 2 % Mortality of the lab strain of Culex pipiens larvae observed after 24 h of treatment at different concentrations of 1, 2, 3, 5, 6, 7, and IMI.

Fig. 3 % Mortality of the lab strain of Culex pipiens larvae observed after 48 h of treatment at different concentrations of 1, 2, 3, 5, 6, 7, and IMI.

Fig. 4 % Mortality of a field strain of Culex pipiens larvae observed after 24 h of treatment at different concentrations of 1, 2, 3, 5, 6, 7, and IMI.

Fig. 5 % Mortality of a field strain of Culex pipiens larvae observed after 48 h of treatment at different concentrations of 1, 2, 3, 5, 6, 7, and IMI.

Structure–action relationship

Neonicotinoids act against nicotinic acetylcholine receptors (nAChRs) through electrostatic interactions and H-bonding, which elevates the toxicity of neonicotinoids.⁴⁷ Neonicotinoids have common molecular features such as an electron-withdrawing group, flexible linkage, aromatic heterocycle, and guanidine or amidine moiety.⁴² The synthesized compounds based on the benzopyridine moiety possess an electron-withdrawing Cl, a halogen, and an electron-withdrawing head that plays a substantial role in binding interactions with the receptor subsites via van der Waals and H-bonding interactions, as well as facilitates π-stacking interactions of the loop C aromatic residue with the amidine moiety.⁴⁸ It was observed that the highest efficacy associated with compound 7 may be due to the presence of the oxadiazole moiety with the SH group that forms two H-bonds with the receptor. This agrees with,⁴⁰ who reported that the presence of sulfanyl acetophenone, sulfanyl acetanilide and phenyl moieties cause the insecticidal activity against Aphis craccivora. The furanone derivative 1 contains two electron-withdrawing O atoms that increase the positivity of the C-2 position. In previous simulations with the insect receptor model, the electronegative moieties of neonicotinoids cause electronic conjugation that facilitates the flow of partial negative charge toward the tips, resulting in π-stacking and hydrogen bonding with the loop D Trp indole of nAChR.⁴⁹ The receptor forms H-bonds between the pyridinyl nitrogen and loop E amino acids and the carbonylimino oxygen with the loop DW79 indole NH.^50a Compound 5 (pyridazinone derivative) exhibited relatively good activity, which was interpreted by,^50b who demonstrated that the nitroimino moiety can be replaced by phenoxycarbonylimino and acylimino variants. The C(=O)–Ph analogs with an electron-donating group on the phenyl ring had higher affinity than those with an electron-withdrawing substituent, suggesting that the benzene plane forms a face-to-edge aromatic interaction with the loop D Trp indole, which was confirmed by³⁹ who proved the activity of certain heterocyclic derivatives containing a pyridine moiety (aromatic heterocycle) against Aphis craccivora Koch.

The presence of the aromatic moiety in the synthesized compounds increased their hydrophobicity, which improves their permeability into the insect integument, thereby enhancing insecticidal activity. The intrinsic insecticidal efficacy and binding affinity of hydrophobic neonicotinoid derivatives against the housefly nicotinic receptor were higher than that of nitro or cyano neonicotinoids via topical application.⁴⁸ Consequently, the increased hydrophobicity of neonicotinoids derivatives increases their penetrability through the insect integument and consequently their insecticidal effectiveness, which allows for diverse methods of exposure and makes them safe for aquatic habitats.³⁹

Conclusion

A new series of N-heterocycles including pyridazinone, oxadiazole, triazolopyridazinone, and triazole derivatives were synthesized from the acid hydrazide via its reaction with certain carbon electrophiles. The potency of the synthesized compounds compared to that of IMI was estimated against lab and field strains of C. pipiens larvae. The tested compounds possess good toxicity, and the furanone, pyridazinone, and oxadiazole derivatives revealed the best insecticidal toxicity relative to IMI against both lab and field strains. The SAR study demonstrated that the halogen or electron-withdrawing substituents play an effective role in binding interactions with the nAChR subunits through van der Waals and H-bonding interactions, and enhance the π-stacking interactions, which effectively increase the activity. The aromatic moiety in the synthesized compounds imparts increased hydrophobicity, which improves their permeability into the insect integument and their binding affinity with the target receptor, thereby increasing their intrinsic insecticidal efficacy. These results are valuable for additional studies on the improvement of novel, effective, and safe insecticides.

Experimental

Instrumentation

Melting points were measured in open capillary tubes on an electrothermal melting point apparatus and were uncorrected. The infrared spectra (ν, cm⁻¹) were recorded using the KBr wafer technique on a Fourier transform infrared Thermo Electron Nicolet iS10 spectrometer (Thermo Fisher Scientific Inc., Waltham, MA) at the Faculty of Science, Ain Shams University. The ¹H and ¹³C NMR spectra (δ, ppm) were measured on a Varian GEMINI (GEMINI, Manufacturing & Engineering Inc., Anaheim, CA, USA) at the Faculty of Science, Cairo University, with tetramethyl silane (TMS) as an internal standard in DMSO-d₆ as a solvent. The mass spectra were recorded on a direct probe controller inlet part to single quadrupole mass analyzer (Thermo Scientific GCMS MODEL (ISQ LT)) using the Thermo X-CALIBUR software at the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Cairo, Egypt. Elemental analyses were performed on a PerkinElmer 2400 CHN elemental analyzer (PerkinElmer, Waltham, MA) at the Faculty of Science, Ain Shams University. Thin-layer chromatography (TLC) was run using TLC aluminum sheets silica gel F254 (Merck, Whitehouse Station, NJ). The 2(3H)-furanone derivative 1 and its corresponding acid hydrazide 2 were synthesized as previously reported.⁴³

2-((2-Chloroquinolin-3-yl)methylene)-N′-(4-methoxybenzylidene)-4-oxo-4-phenylbutanehydrazide (3). A solution of the hydrazide 2 (1 g, 3 mmol) and 4-methoxybenzaldehyde (0.3 mL, 3 mmol) in dioxane (10 mL) was heated under reflux for 8 h. After cooling, the solid obtained was collected and recrystallized from a benzene/ethanol mixture (2 : 1) to provide orange crystals, mp. 250–252 °C. IR (KBr, ν, cm⁻¹): 3300 (NH), 1700 (C=O ketone), 1658 (C=O amide), 1607 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 12.09 (br.s, 1H, NH, exchangeable), 9.34 (s, 1H, CH=N), 8.64 (s, 1H, C4–H quinoline), 7.92 (s, 1H, CH=), 7.83–6.99 (m, 13H, Ar–H), 3.81 (s, 3H, OCH₃), 3.35 (s, 2H, CH₂). ¹³C NMR (75 MHz, DMSO-d₆): 160.87 (C=O), 156.57 (C=O), 143.27 (C=N), 140.05 (C=N), 139.15, 132.09, 130.88, 130.19, 129.34, 129.11, 128.37, 128.33, 127.91, 127.70, 126.27, 125.44, 122.43, 119.41, 115.19, 114.46 (Ar–C + CH=), 63.08 (CH₃), 40.33 (CH₂). MS, m/z (%): 486 (M + 2, 12.09), 484 (M⁺, 17.5), 371 (17.46), 367 (23.37), 292 (17.15), 275 (94.52), 183 (15.09), 141 (18.55), 103 (27.02), 86 (33.7), 76 (70.97), 71 (73.14), 63 (41.18), 43 (96.2), 40 (100). Anal. calcd for C₂₈H₂₂ClN₃O₃ (483.95): C, 69.49; H, 4.58; N, 8.68. Found: C, 69.32; H, 4.44; N, 8.70%.

N′-((1H-Indol-3-yl)methylene)-2-((2-chloroquinolin-3-yl)methylene)-4-oxo-4-phenylbutanehydrazide (4). A solution of the hydrazide 2 (1 g, 3 mmol) and 3-formylindole (3 mmol) in dioxane (10 mL) was refluxed for 8 h. After cooling, the solid obtained was collected and recrystallized from dioxane to provide orange crystals, mp. 310–312 °C. IR (KBr, ν, cm⁻¹): 3245 (NH), 1685 (C=O ketone), 1650 (C=O amide), 1634 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 12.14 (br.s, 1H, NH, exchangeable), 11.95 (br.s, 1H, NH, exchangeable), 9.45 (s, 1H, CH=N), 8.64 (s, 1H, C4–H quinoline), 7.97–6.96 (m, 15H, Ar–H + CH=), 3.55 (s, 2H, CH₂). ¹³C NMR (75 MHz, DMSO-d₆): 166.61 (C=O), 161.18 (C=O), 153.78 (C=N), 149.01 (C=N), 139.74, 138.92, 137.22, 132.52, 131.57, 130.41, 129.61, 129.29, 128.91, 128.55, 128.14, 126.86, 125.07, 124.09, 122.68, 122.24, 121.77, 120.66, 119.58, 115.09, 112.06, 111.40 (Ar–C + CH=), 40.33 (CH₂). Anal. calcd for C₂₉H₂₁ClN₄O₂ (492.96): C, 70.66; H, 4.29; N, 11.37. Found: C, 70.49; H, 4.11; N, 11.40%.

4-((2-Chloroquinolin-3-yl)methyl)-6-phenylpyridazin-3(2H)-one (5). A solution of the hydrazide 2 (3 mmol) and pentan-2,4-dione (3 mmol) in dioxane (10 mL) was refluxed for 6 h. After cooling, the solid obtained was filtered off and recrystallized from an ethanol/dioxane mixture (2 : 1) and found to be the pyridazinone 6, which was identical in all respects (IR, mp, mixed mp, and TLC) with an authentic sample prepared by boiling the hydrazide 2 in n-butanol for 3 h.⁴³

1-Acetyl-4-((2-chloroquinolin-3-yl)methylene)-6-phenyl-1,4-dihydropyridazin-3(2H)-one (6). A suspension of the hydrazide 2 (1 g, 3 mmol) in acetic anhydride (10 mL) was refluxed for 3 h. After cooling, the solid obtained was collected and recrystallized from benzene to provide orange crystals, mp. 240−242 °C. IR (KBr, ν, cm⁻¹): 3157 (NH), 1731, 1671 (C=O amide), 1608 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 12.09 (br.s, 1H, NH, exchangeable), 8.67 (s, 1H, C4–H quinoline), 7.92–7.21 (m, 10H, Ar–H + CH=), 7.13 (s, 1H, C5–H pyridazine), 2.36 (s, 3H, CH₃). ¹³C NMR (75 MHz, DMSO-d₆): 170.95 (C=O), 168.52 (C=O), 161.01 (C=N), 146.35, 140.56, 139.14, 131.97, 130.29, 129.43, 129.06, 128.35, 127.22, 127.01, 126.37, 126.33, 122.33, 119.45, 115.10 (Ar–C + CH=), 24.57 (CH₃). MS, m/z (%): 392 (M + 2, 43.80), 390 (M⁺, 15.11), 361 (40.57), 293 (16.71), 250 (10.17), 234 (22.31), 225 (49.47), 183 (37.24), 161 (42.10), 123 (41.57), 111 (51.43), 87 (33.95), 76 (64.72), 69 (40.25), 41 (100). Anal. calcd for C₂₂H₁₆ClN₃O₂ (389.84): C, 67.78; H, 4.14; N, 10.78. Found: C, 67.60; H, 4.01; N, 10.81%.

3-(2-(5-Mercapto-1,3,4-oxadiazol-2-yl)-4-oxo-4-phenylbut-1-en-1-yl)quinolin-2(1H)-one (7). Carbon disulfide (5.5 mmol) was added to a solution of hydrazide 2 (5 mmol) in alc. NaOH (17 mL) and the reaction mixture was heated at ∼90 °C for 12 h. The reaction mixture was left overnight. The deposited solid was collected and recrystallized from a benzene/ethanol mixture (2 : 1) to afford off-white crystals, mp. 270–272 °C. IR (KBr, ν, cm⁻¹): 3162 (NH), 1656 (C=O), 1607 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 13.20 (br.s, 1H, SH, exchangeable), 11.85 (br.s, 1H, NH, exchangeable), 7.83–7.11 (m, 11H, Ar–H + C4–H quinoline + CH=), 3.77 (s, 2H, CH₂). ¹³C NMR (75 MHz, DMSO-d₆): 161.70 (C=O), 160.69 (C=O), 143.93 (C=N), 140.81 (C=N), 138.07, 137.46, 134.95, 129.63, 129.60, 129.06, 128.88, 128.50, 128.31, 127.51, 125.64, 121.76, 119.28, 114.86 (Ar–C + CH=), 30.02 (CH₂). MS, m/z (%): 389 (M⁺, 34.88), 388 (M −- 1, 11.97), 361 (M–CO, 41.43), 306 (40.71), 299 (45.09), 286 (25.33), 261 (30.7), 249 (34.31), 243 (37.62), 205 (27.49), 155 (18.41), 75 (100), 56 (67.43), 56 (67.43), 44 (33.32). Anal. calcd for C₂₁H₁₅N₃O₃S (389.43): C, 64.77; H, 3.88; N, 10.79. Found: C, 64.61; H, 3.93; N, 10.76%.

3-((3-Mercapto-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-8(7H)-ylidene)methyl)quinolin-2(1H)-one (9). To a stirred solution of hydrazide 2 (5 mmol) in ethanol (30 mL), potassium hydroxide (5.5 mmol in 5 mL ethanol) was added at ambient temperature, and carbon disulfide (5.5 mmol) was then added dropwise. The reaction mixture was further stirred at ambient temperature for 24 h. The solid obtained was collected by filtration, washed with dry ether, and dried to afford the potassium salt 8 that was used without further purification. A solution of potassium salt 8 (5 mmol) and hydrazine hydrate (5 mmol, 80%) in water (15 mL) was heated under reflux until all hydrogen sulfide evolved (∼8 h). The precipitated solid was collected and crystallized from an ethanol/dioxane mixture (2 : 1) to afford yellow crystals, mp. 320–322 °C (decomp.). IR (KBr, ν, cm⁻¹): 3160 (NH), 1656 (C=O), 1609 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 13.15 (br.s, 1H, SH, exchangeable), 11.81 (br.s, 1H, NH, exchangeable), 7.80–7.14 (m, 11H, Ar–H + C4–H quinoline + CH=), 3.76 (s, 2H, CH₂). Anal. calcd for C₂₁H₁₅N₅OS (325.39): C, 65.44; H, 3.92; N, 18.17. Found: C, 65.31; H, 3.85; N, 18.20%.

3-(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)-4-(2-chloroquinolin-3-yl)-1-phenylbut-3-en-1-one (10). A solution of potassium salt 8 (5 mmol), prepared from the previous step, and hydrazine hydrate (5 mmol, 80%) in ethanol (15 mL) was heated under reflux until all hydrogen sulfide evolved (∼8 h). The precipitated solid was collected and crystallized from dioxane to afford yellow crystals, mp. 252–254 °C. IR (KBr, ν, cm⁻¹): 3250, 3161 (NH₂), 1705 (C=O), 1637 (C=N). ¹H NMR (300 MHz, DMSO-d₆, δ, ppm): 11.96 (br.s, 1H, NH, thiolactam form, exchangeable), 8.05 (s, 1H, C4–H quinoline), 7.77–7.12 (m, 10H, Ar–H + CH=), 6.71 (s, 1H, SH, thiolactim form, exchangeable), 4.43 (br.s, 2H, NH₂, exchangeable), 3.27 (s, 2H, CH₂). MS, m/z (%): 424 (M + 2, 17.89), 422 (M⁺, 33.43), 419 (40.37), 393 (22.67), 354 (34.02), 331 (49.44), 315 (75.39), 300 (46.12), 286 (45.06), 246 (40.65), 221 (39.56), 193 (40.51), 142 (61.61), 97 (39.40), 69 (57.66), 43 (100). Anal. calcd for C₂₁H₁₆ClN₅OS (421.90): C, 59.78; H, 3.82; N, 16.60. Found: C, 59.64; H, 3.71; N, 16.70%.

Insecticidal activity

Breeding of mosquitoes. The laboratory strain of Culex pipiens was reared in the mosquito insectary at the Entomology Department, Faculty of Science, Ain Shams University. The insectary was maintained at 70 ± 10%, relative humidity 27 ± 3 °C, and a cycle of dark and light (10 h : 14 h).⁵¹ C. pipiens breeding went through three aquatic stages: egg, larva, and pupa, in addition to flying adult. Egg rafts were placed in enamel bowls containing dechlorinated water. The newly hatched larvae were fed on a mixture of dog biscuits and yeast powder (in a ratio of 3 : 1). The pupae were collected daily and transferred to glass jars containing dechlorinated water and then placed in 25 × 25 × 25 screened cages for adult breeding. Adults were provided daily with cotton pads soaked in a 10% sugar solution. Females were fed pigeons for a blood meal.⁵⁵ The field strain of C. pipiens larvae was collected from Mansoura Canal, Abou Rawash, Giza, Egypt.

Larvicidal bioassay. The larvicidal activities of the synthesized compounds (1, 2, 3, 5, 6, 7) and the reference insecticide imidacloprid (IMI) were assessed against C. pipiens larvae according to ref. 52 with some modifications. For the preparation of a 1000 ppm stock solution, the tested compounds were dissolved in dimethyl sulfoxide (DMSO). Six concentrations of each compound were prepared by diluting them with dechlorinated water, as follows: 10, 7.5, 5, 2.5, 1, and 0.5 μg mL⁻¹ for the lab strain treatments, and each concentration was replicated three times. For control, three replicates of a DMSO and dechlorinated water mixture were used. Twenty third instar C. pipiens larvae were placed in each concentration replicate, and likewise for the control.⁴¹ In the same manner, the field strain third instar C. pipiens larvae were subjected to six concentrations of the tested compounds viz., 100, 75, 50, 25, 10, and 5 μg mL⁻¹ and the control replicates. Mortality rates were recorded after exposure times of 24 and 48 h.

Statistical analysis. The data of larval mortality were analyzed using probit analysis⁵³ via a statistics (LDP-line) package to calculate the LC values with 95% fiducial limits of lower and upper confidence limit, slope, standard error, chi-square, and correlation coefficient.

Conflicts of interest

No potential conflict of interest was reported by the author(s).

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the Research Groups Program under grant number RGP.2/183/43.

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Footnote

† Electronic supplementary information (ESI) available. See https://doi.org/10.1039/d2ra02388a

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