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Abstract

Objective: In this study, a series of synthetic hydroxylated (5-10) and prenylated (10-17) acetophenones, chalcones (18-20) and a flavone (21) have been synthesized and evaluated on the nematode Meloidogyne javanica. Additional phenolic compounds, including salicylic acid, isopropyl salicylate, thymol, carvacrol, cumic acid, eugenol, vanillin, and vanillic acid (22-29), were also tested. Methods: Compounds 5-21 have been synthesized by a sequence of reactions and were isolated and identified by ¹H-NMR, ¹³C-NMR, and HRMS. The in vitro nematicidal effects of the compounds were tested on J2 juveniles. The nematicidal activity was confirmed by their egg hatching inhibition effects, tested at the minimum lethal concentration (minimum dose to give 100% J2 mortality). Results: Compounds 5-18 have been previously reported and 19-21 are described here for the first time. The 2´-hydroxylated acetophenones (5-9) showed strong nematicidal effects, being 7-9 the most active. Salicylic (22) and cumic (26) acids were effective compounds. Compounds 7, 12, 22-26, active on M. javanica J2 juveniles, were also egg hatching inhibitors. Conclusions: A C-2/C-4 dihydroxylation or C-2/C-4/C-3 trihydroxylation of the acetophenone moiety improved the activity, while introducing a hydrophilic isoprene chain (10-17) eliminated the effect, with only one prenylated acetophenone (12) being active. Among the additional phenolic compounds (22-29), these with a carboxyl group instead of the acyl side were better nematicides. These results generate molecular leads for developing new nematicidal phenolic compounds.

Keywords

nematicidal activity acetophenone phenol structure-activity

Introduction

Plant-parasitic nematodes cause substantial economic losses to agriculture worldwide and threaten the sustainable development of modern agriculture,¹ with estimated annual economic losses of $157 billion worldwide.^2,3

Root-knot nematodes (Meloidogyne sp.) are among the groups with the highest pathogenic capacity and the largest number of hosts. Specifically, Meloidogyne javanica is an important pathogen of vegetables worldwide, impacting both the quantity and the quality of marketable products.⁴ On the other hand, the control of Meloidogyne has been mainly based on chemical nematicides. Despite their effectiveness, most of these compounds are withdrawn from the market because of their toxicity and severe impact on the environment and human health.

Therefore, developing new nematicidal agents with high efficiency and low toxicity is essential.¹ In this context, natural products (NPs) have gained interest in recent years due to their potential to control soil nematodes and because NPs provide diverse structural models for the bioinspired synthesis of new nematicidal compounds.⁵

Phenolic compounds are elicitated by root-knot nematodes^6,7 and have been associated with plant resistance to the pathogens in relation to the hypersensitivity reaction.^8,9 Furthermore, phenolic compounds can attract Meloidogyne species second-stage juveniles¹⁰ and also have direct nematicidal effect.^5,9,11 Among natural and synthetic nematicidal phenolic compounds are aldehydes,¹² lactones, acetophenones, and chalcones,^13–15 phenolic terpenes such as thymol and carvacrol, eugenol,¹⁵ and phenolic acids such as salicylic.¹⁶

The phenylketone group is a part of many natural molecules, such as flavonoids, chromones, some alkaloids, and acetophenones, and show a wide range of biological activities.^17,18 Natural acetophenones are involved in plant defenses^19,20 and usually have phenolic hydroxy groups and additional free or cyclized isoprenyl units. The nematicidal potential of acetophenones substituted in the 4′position with electrophilic groups¹⁴ and haloacetophenones²¹ has been explored, and the nematicidal effect of 2,4-dihydroxyacetophenone has been reported.⁹

On the other hand, chalcones, (E)-1,3-diaryl-2-propen-1-ones, are characterized by two aromatic rings with an array of different substituents, and have biological activities including antimalarial, antiinflammatory, antibacterial, antiprotozoal, antifilarial, antifungal, and mosquito larvicidal.²² Natural and synthetic chalcones have also been reported as being nematicidal. For example, E-chalcone exhibited activity against Globodera pallida,²³ while the ferrocenyl chalcones (2E)-1-(4-methylphenyl)-3-ferrocenyl-prop-2-en-1-one and (2E)-1-(4-methoxyphenyl)-3-ferrocenyl-prop-2-en-1-one decreased the incidence of M. incognita in tomato plants.¹³ However, organic chalcones had better nematicidal activity than ferrocenyl chalcones against the model nematode Caenorhabditis elegans.²⁴ Other synthetic chalcones such as 2,4,5-trimethoxy-4´-nitrochalcone,²⁵ 1-(4-fluoro-phenyl)-3-phenyl-propenone and 1,3-diphenyl-propenone,²⁶ (1E,4E)-1,5-di(4-nitrophenyl)-2-butylpenta-1,4-dien-3-one²⁷ were effective against M. exigua, M. graminicola, and M. incognita, and according to in silico studies, the target enzyme is cytochrome P450.²⁷

In a recent work, 26 phenolic molecules, including acetophenones and chalcones, have been synthesized to study the importance of the hydroxyl and isoprenyl substituents and the pyran-4-one systems in their trypanocidal activity.¹⁸ However, their nematicidal activity has not been explored.

In this study, a series of hydroxylated and prenylated acetophenones and chalcones have been synthesized and evaluated on the nematode M. javanica. Additional phenolic compounds, including salicylic acid, isopropyl salicylate, thymol, carvacrol, cumic acid, eugenol, vanillin, and vanillic acid, were also tested to increase the chemical diversity and further understand the nematicidal structure-activity relationships of phenolic compounds.

Results and Discussion

Compounds 5-18 were synthesized by a sequence of reactions¹⁸ isolated and purified from the reaction mixtures by dichloromethane extraction and chromatographic separation and identified by ¹H-NMR, ¹³C-NMR, and HRMS. The synthetic steps are summarized in Figure 1.

Figure 1.

Synthetic strategy for preparing derivatives 5-21. Reagents and conditions: (I) Ac₂O, BF₃-Et₂O, 50 °C, 12 h, Yield 16.5-56%; (II) 3-Methyl-2-buten-1-ol, BF₃-Et₂O, room temperature, 24 h, Yield 5.1-12.3%; (III) K₂CO₃, MOMCl, ACN, 60 °C, MW, 1 h, Yield 48.0-77.5%; (IV) KOH/EtOH, 40 °C, 12 h, Yield 46.3-77.5%.

Compounds 5-18 have been previously synthesized¹⁸ and compounds 19-21 are described here for the first time.

Additional compounds (22-29) were explored to increase the chemical diversity of the tested phenols (Figure 2).

Figure 2.

Chemical structures of additional phenolic compounds tested.

Considering the importance of phenolic compounds in the nematode plant interactions, we have studied the nematicidal activity of 5-21 with an acetophenone moiety since this pharmacophore is common in many bioactive NPs. Table 1 shows the in vitro nematicidal effects of the compounds tested. Compounds with mortalities below 50% were not further tested in dose-response experiments.

Table 1.

Effects of Compounds 1-29 (at 0.5 mg/ml) on Mortality (%) of Second-stage Juveniles (J2) of Meloidogyne javanica and their Effective Doses (LD₅₀, LD₉₀) After 72 h.

Compound	J2 Mortality (%)^a	LD₅₀^b	LD₉₀^b
Compound	J2 Mortality (%)^a	mg/mL (95% CL)^c
1	8.01± 1.61	>0.5	>0.5
2	0	>0.5	>0.5
5	82.86± 5.18	0.323 (0.309-0.338)	0.532 (0.508-0.561)
6	84.50± 0.71	0.341 (0.327-0.357)	0.553 (0.528-0.582)
7	100.00± 0.00	0.109 (0.102-0.115)	0.219 (0.207-0.234)
8	100.00± 0.00	0.194 (0.185-0.204)	0.319 (0.301-0.341)
9	100.00± 0.00	0.148 (0.140-0.158)	0.263 (0.246-0.283)
10	9.96± 2.10	>0.5	>0.5
11	12.05± 1.13	>0.5	>0.5
12	100± 0.00	0.171 (0.170-0.180)	0.240 (0.230-0.250)
13	8.37± 1.17	>0.5	>0.5
14	9.45± 1.83	>0.5	>0.5
15	8.95± 1.34	>0.5	>0.5
16	19.78± 2.24	>0.5	>0.5
17	12.37± 3.16	>0.5	>0.5
18	12.61± 2.74	>0.5	>0.5
19	15.32± 4.11^d	>0.25	>0.25
20	1.27± 1.19	>0.5	>0.5
21	4.57± 1.19	>0.5	>0.5
22	100± 0.00	0.085 (0.082-0.089)	0.121(0.116-0.127)
23	100± 0.00	0.144 (0.139-0.150)	0.229 (0.221-0.240)
24	100± 0.00	0.143 (0.131-0.143)	0.219 (0.209-0.230)
25	100± 0.00	0.152 (0.146-0.155)	0.212 (0.205-0.219)
26	100± 0.00	0.091 (0.083-0.099)	0.231 (0.216-0.249)
27	13.12 ± 2.5	>0.5	>0.5
28	24.58± 4.0	>0.5	>0.5
29	3.27± 0.77	>0.5	>0.5

^aCorrected according to Scheider-Orelli's formula. Values are means of four replicates.

^bLethal doses to give 50% and 90% mortality (Probit analysis).

^c95% Confidence Limits.

^dCompound 19 was tested at 0.25 mg/ml.

The phenolic compounds resorcinol (1) and pyrogallol (2), used as starting compounds for the synthesis of the acetophenones, were not nematicidal, as previously shown.⁹ However, some modifications of the acetophenones significantly varied the activity. Simple 2´-hydroxylated acetophenones (5-9) showed strong nematicidal effects against M. javanica J2, with LC₅₀ values between 0.1-0.3 mg/mL. The most active compounds were 7 (EC₅₀= 0.10 mg/mL), 9 (LC₅₀= 0.15 mg/mL) and 8 (LC₅₀= 0.20 mg/mL). Significant activity was also found for compounds 5 and 6, which exhibited a similar effect (LC₅₀= 0.3 mg/mL) (Table 1). It is interesting to note that 7 was obtained in a high yield (50%). A p-OH group with respect to the carbonyl group was essential for the activity (compounds 7 and 9), while the possible formation of another hydrogen bond reduced this effect (compound 6).

Prenylation of the acetophenones removed the activity in almost all cases. Thus, compounds of the type 2′-hydroxy-prenyl acetophenones (10-17) were not nematicidal, including compound 10, a prenylated analog of the active compound 7. However, compound 12 (a C-3 prenylated-(C-2/C-5) dihydroxy compound) was nematicidal (LC₅₀= 0.17 mg/mL), being more effective than the hydroxylated parent 8. In addition, derivatization of the second hydroxy group in the acetophenone system with a methoxymethoxy group also removed the activity (16 vs the bioactive 12). Overall, introducing hydrophilic groups like an isoprene chain on the acetophenone moiety (compounds 10-17) led to the loss of the nematicidal activity, as previously reported for this chemical class.²³ A more complex acetophenone system, such as the one in substituted chalcones 18-20 and flavone 21, did not contribute to the nematicidal activity (Table 1). Therefore, the nematicidal activity depended on the hydroxylation of the acetophenones and varied with their position, indicating a strong structure-activity relationship for these products. Prenylation and additional substitution resulted in the loss of activity.

Moreover, additional compounds (22-29) were explored to increase the chemical diversity of tested phenols. Phenols with a carboxyl group were better nematicides than compounds with an acyl side. Thus, salicylic acid (22) resulted in the most effective nematicidal compound (LC₅₀= 0.08 mg/mL), followed by cumic acid (26), with a p-isopropyl group (LC₅₀= 0.09 mg/mL), isopropyl salicylate (23) (LC₅₀= 0.14 mg/mL), thymol (24), and carvacrol (25) (LC₅₀= 0.14 and 0.15 mg/mL, respectively) (Table 1). Eugenol (27), with an allylphenol system, did not show significant effects under the experimental conditions of this work. The need for a 2′-OH group is shown by the lack of activity of vanillic acid (29), while its aldehyde, vanillin (28), or the propyl phenol, eugenol (27) also lacked nematicidal activity.

The nematicidal action of the most effective compounds (7, 12, 22-26) was further confirmed by their egg hatching inhibition effects, tested at the minimum lethal concentration (MLC, minimum dose to give 100% J2 mortality) (Table 2). All these compounds significantly reduced the number of hatched J2 s respect to the control for each incubation time (75%-94% total suppression) when tested at MLC concentrations (0.25 mg/ml except for 22 with a MLC value of 0.12 mg/ml). Therefore, salicylic acid (22) was the most effective egg hating inhibitor (99% suppression after 14 days of immersion and 94% total inhibition). Cumic acid (26) had a delayed effect on hatching (lowest suppression rates for immersion times 0 and 7) that increased with immersion time (Table 2). These results confirm the strong nematicidal activity of these compounds since the egg hatching suppression effect indicates the ability of a compound to penetrate the gelatinous mass matrix and then affect the nematode eggs.²⁸

Table 2.

Effects of the Nematicidal Compounds 7, 12, and 22-26 on Meloidogyne javanica Egg Masses with Time Relative Suppression Rate, RSR and Total Suppression Rate, TSR). These Compounds were Tested at their Minimal Lethal Concentration (MLC, mg/mL) on J2.

Compound	MLC	Hatched J2 and RSR (%) with time¹										TSR (%)
Compound	MLC	0		7		14		21		28		TSR (%)
7	0.25	24.7± 3.7²^,a	85³	1025.2± 14.3^a	80	444.3± 19.3^a	84	122.5± 13^a	88	16.72± 4^a	89	85
12	0.25	16.5± 2^a	90	1230.4± 21^b	76	499.8± 33.2^ab	82	40.8± 15.2^b	96	1.5± 0.7^b	99	89
22	0.12	21.5± 4.1^a	87	512.6± 12.7^c	90	111± 10^c	96	10.2± 1.7^c	99	1.5± 0.2^b	99	94
23	0.25	34.6± 5.3^b	79	1076.4± 18.2^a	79	527.6± 18.9^b	81	61.2± 13.4^b	94	6± 1.3^c	96	86
24	0.25	36± 3.9^b	79	1127.7± 14.4^a	78	277.7± 9.3^d	90	234.8± 14.1^d	77	10.64± 4.7^cd	93	83
25	0.25	39.6± 5.5^b	76	1178.9± 17.6^b	77	638.7± 11.5^e	77	428.8± 9.9^e	58	18.24± 3^a	88	75
26	0.25	122.1± 10.2^c	26	1486.5± 23.1^d	71	361± 12.8^f	87	214.4± 18.5^d	79	13± 1.9^d	91	78
Control		165± 7.9^d		5126± 35,7^e		2777± 20.1^g		1021± 14.3^f		152± 11.4^e

¹Time 0: Five days of incubation. Subsequent times: number of days of immersion in water after time 0.

²Values are mean± standard error of hatched juveniles from three egg masses/four replicates. Values within the same column followed by different lower case letters are significantly different according to ANOVA analysis followed by Least Significant Difference Test (P < 0.05).

³Each value represents the percent relative suppression rate (number of J2 in water control—number of J2 in test solution) / number of J2 in water control× 100).

This is the first report on the nematicidal and egg hatching inhibition effects of compounds 5, 6, 8, 9, and 12 and the egg hatching inhibition effect of 7. Cumic acid (26), one of the most active compounds found in this study, has been extensively described as an antifungal with plant defense induction effects;^29–33 however, this is the first report on its toxic and egg hatching inhibition effects against root-knot nematodes.

Several compounds studied here such as 7, 22, 24, 25, 27, and 28 have been previously reported as having direct or indirect nematicidal effects. Compound 7 (2,4-dihydroxyacetophenone) had strong nematicidal effects against M. incognita.⁹ Salicylic acid (22) showed indirect nematicidal effects such as the Mi-1-mediated defense response against root-knot nematode in tomato,³⁴ soil or leaf application with 22 increased enzymatic activity and phenolic compounds in tomato roots infected with M. javanica³⁵ and seed treatments with 22 reduced root-knot nematode (M. javanica) reproduction and population in tomato.³⁶ Salicylic acid (22) also had direct in vitro nematicidal effects against M. incognita J2 and eggs.^15,16

Carvacrol (25) and thymol (24) were toxic to C. elegans,³⁷ Ditylenchus dipsaci,³⁸ and M. javanica³⁹ and inhibited egg hatching of M. incognita^40,41 and M. javanica.⁴² Thymol (24) acted at synthetic GABA receptors from M. incognita using a Xenopus oocyte expression system.⁴³ These results highlight the importance of the presence of a hydroxy and a p-isopropyl group for the activity of these phenolic compounds. For example, p-cymene, a carvacrol-thymol precursor lacking the hydroxy group, showed moderate nematicidal activity against M. incognita (LC₅₀ value of 0.436 mg/mL)⁴⁴ and was inactive to M. javanica at 0.5 mg/ml.⁴⁵

Eugenol (27) was nematicidal to D. dipsaci³⁸ and M. incognita.⁴⁶ However, in this work, eugenol (27) was not active, probably due to the different experimental conditions (25 times more J2/mL used here for the same concentration reported). Vanillin (28) was a mild toxicant to C. elegans³⁷ but here resulted inactive against M. javanica.

Conclusions

Developing new nematicidal agents with high efficiency and low toxicity is essential. In this context, NPs have gained interest in recent years due to their potential to control soil nematodes and their diverse structural models for the bioinspired synthesis of new nematicidal compounds. In the search for substances with nematicidal activity against M. javanica, 22 synthesized compounds were tested to determine the role of hydroxy groups and an isoprene residue (5 carbon atoms) in an acetophenone system. Among the hydroxylated acetophenones (5-9), the most active ones were 7, 9, and 8, followed by 5 and 6, with similar effects. Therefore, a C-2/C-4 hydroxy substitution resulted in the highest activity (7), followed by trihydroxylation at C-2/C-4/C-3 (9), while hydroxylation at C-2/C-6 (5) or trihydroxylation at C-2/C-4/C-6 (6) was not as effective. Overall, introducing hydrophilic groups on the acetophenone moiety (compounds 10-17) led to the loss of nematicidal activity. Only compound 12 was active, being more effective than the hydroxylated parent, while none of the chalcones (18-21) were active. Additional compounds (22-29) were explored to increase the chemical diversity of the tested phenols. Phenols with a carboxyl group, such as salicylic (22) and cumic acid (26), resulted in the most effective nematicidal compounds, followed by isopropyl salicylate (23), thymol (24), and carvacrol (25). The nematicidal action of these compounds (7, 12, 22-26) was further confirmed by their egg hatching inhibition effects, with 22 being the most effective.

Our results confirm previous reports about the effect of hydrophilic groups in the decrease of the nematicidal action of acetophenones. It also highlights the importance of a benzoic acid core group and the need for a 2′-OH type group to highlight the activity of phenols.⁴⁸ Moreover, this study contributes to the generation of new structure leads for the development of new nematicidal compounds, such as hydroxylated acetophenones (5-9), acetophenones prenylated at C-5 (12), phenolic acids (22, 26), and alkylated phenols with a p-isopropyl group (24, 25). These compounds are also effective inhibitors of nematode egg hatching and relatively easy to obtain from natural or synthetic sources. Furthermore, some are constituents of various foods and components of essential oils, suggesting low toxicity. Further research should be carried out to test for the in vivo nematicidal effects of these compounds along with their environmental fate. Additionally, it is also important to further study the quantitative structure-activity relationship of these compounds for a comprehensive analysis of target identification and the mechanism of action.^49,50

Materials and Methods

General Procedure

All commercially available reagents and solvents were obtained from commercial suppliers and used without further puriﬁcation. Phenols 1-4 and 22-29 were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Thin-layer chromatography, silica gel 60 F254-impregnated aluminum sheets (0.25 mm, Merck, Darmstadt, Germany) was used to check the progress or reactions, and compounds were detected under UV light (254, 360 nm) after spraying with vanillin (3% in H₂SO₄) and heating at 110 °C. The chromatographic separations were performed using preparative column chromatography with silica gel 60 (200-300 mesh, Merck, Darmstadt, Germany). The melting points were determined using a Mel-Temp apparatus (Electrothermal, Staffordshire, UK). ¹H, ¹³C, and 2D NMR spectra of the synthetic compounds were recorded on a Bruker Fourier 300 spectrometer (Bruker Bio-Spin GmbH, Rheinstetten, Germany) operating at 300 MHz for ¹H and 75 MHz for ¹³C-NMR, using CDCl₃ (Sigma, St Louis, Mo, USA) as the solvent, and TMS as an internal standard. Chemical shifts (δ) are reported in ppm, and the coupling constants (J) are reported in Hz. High-resolution mass spectra were obtained using a UHR-QqTOF (Ultra-High Resolution Qq-Time-Of-Flight) mass spectrometer (Impact II-Bruker), with an electrospray ionization source in positive ion mode.

Chemical Synthesis

Synthesis and prenylation of 2-hydroxyacetophenone derivatives: The synthesis of the acetophenones 5-9 from the phenol derivatives (1-4) and the prenylated 2-hydroxy-acetophenones 10-13 from acetophenones 5-9 was conducted as described.¹⁷ Briefly, the respective phenol derivatives were dissolved in acetic anhydride and then treated with boron trifluoride-diethyl ether (BF₃-Et₂O). The protection of hydroxyl groups of the prenylated 2-hydroxy-acetophenones 10-13 was conducted as described.¹⁸ Briefly, the respective 2-Hydroxyacetophenone derivatives were dissolved individually in K₂CO₃/ACN, and methoxymethyl chloride (MOMCl) was added dropwise.

Preparation of prenylated chalcones: The synthesis of the prenylated chalcones 18-21 from the methoxy-methylated acetophenone (14) and benzaldehyde derivatives was carried out as described.¹⁸ Briefly, the 2-hydroxyacetophenone derivatives were dissolved individually in 3-methyl-2-buten-1-ol, and BF₃-Et₂O was added dropwise.¹⁰ All compounds were purified by column chromatography.

NMR-spectroscopy and Mass Spectrometry

Compounds 5-18 have been previously reported.¹⁸ The new compounds 19-21 are described below.

Compound (19) (for additional information, see Online Resource 1)

3-(4-(dimethylamino)phenyl)-1-(2-hydroxy-4-(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)prop-2-en-1-one: Yield 77.5%, m.p.: 112 °C-113 °C; IR (KBr) ʋ/cm:1. ¹H NMR (300 MHz, CDCl₃) δ 13.54 (s, 1H), 7.86 (d, J= 15.3 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J= 8.8 Hz, 1H), 7.37 (d, J= 15.2 Hz, 1H), 6.74 (d, J= 8.6 Hz, 1H), 6.63 (s, 1H), 5.33-5.17 (m, 3H), 3.47 (s, 2H), 3.29 (d, J= 7.1 Hz, 2H), 3.06 (s, 6H), 2.17 (s, 6H), 1.76 (s, 6H).¹³C-NMR (75 MHz, CDCl3) δ 191.97, 164.65, 161.01, 145.06, 132.74, 130.60, 129.96, 122.54, 121.67, 114.45, 112.39, 112.14, 102.14, 93.96, 56.35, 40.56, 30.99, 28.42, 25.85, 17.92. HRMS (ESI) m/z, calculated for C₂₄H₃₀NO₄ [M + H]⁺ 396.2169; found 396.2176

Compound (20) (for additional information, see Online Resource 2)

4-(3-(2-hydroxy-4-(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)-3-oxoprop-1-en-1 yl)benzonitrile: Yield 72.3%, m.p.: 121-122 °C; IR (KBr) ʋ/cm:1. ¹H NMR (300 MHz, CDCl₃) δ 13.09 (s, 1H), 7.88 (d, J= 15.6 Hz, 1H), 7.84 (s, 1H), 7.78 (s, 4H), 7.70 (d, J= 15.9 Hz, 1H), 7.64 (s, 1H), 6.71 (s, 1H), 5.30 (sbr, 3H), 3.53 (s, 3H), 3.29 (d, J= 6.9 Hz, 2H), 1.80 (s, 3H), 1.79 (s, 3H).¹³C-NMR (75 MHz, CDCl₃) δ 191.09, 165.18, 162.03, 141.53, 139.21, 133.02, 132.76, 130.06, 128.78, 123.82, 122.24, 118.45, 114.06, 113.52, 102.26, 94,02, 56.46, 28.47, 25.84, 17.95. HRMS (ESI) m/z, calculated for C₂₃H₂₄NO₄ [M + H]⁺ 379.1771; found 379.1778

Compound (21) (for additional information, see Online Resource 3)

7-(methoxymethoxy)-6-(3-methylbut-2-en-1-yl)-2-(4-nitrophenyl)-4H-chromen-4-one: Yield 75.5%, m.p.: 157-158 °C; IR (KBr) ʋ/cm:1. ¹H NMR (300 MHz, CDCl₃) δ 8.23 (d, J= 8.7 Hz, 1H), 7.97 (d, J= 8.7 Hz, 1H), 7.54 (s, 1H), 7.01 (s, 1H), 6.73 (s, 1H), 5.35 (s, 1H), 5.26 (t, J= 7.2 Hz, 1H), 3.52 (s, 1H), 3.29 (d, J= 7.1 Hz, 1H), 1.75 (s, 3H), 1.69 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ 183.05, 167.38, 163.14, 149.49, 147.38, 139.01, 134.05, 131.57, 128.09, 124.79, 123.94, 121.01, 114.15, 108.17, 97.56, 94.42, 56.58, 28.31, 25.89, 17.79. HRMS (ESI) m/z, calculated for C₂₂H₂₂NO₆ [M + H]⁺ 396.1441; found 346.1443

Nematicidal Activity

A field-selected M. javanica population from Barcelona, Spain, was maintained on tomato plants (Solanum lycopersicum L. var. Marmande) cultivated in pot cultures in environmentally controlled growth chambers (at 25± 1 °C, >70% relative humidity). Egg masses of M. javanica were handpicked from infected tomato roots 2 months after inoculation of the seedlings. Second-stage juveniles (J2) were obtained by incubating egg masses in a water suspension at 25 °C for 24 h.

In vitro Effects on Juveniles J2

Second-stage juveniles (J2) were obtained from hatched eggs by incubating egg masses in a water suspension at 25 °C for 24 h. evaluated as described.⁷ Briefly, 100 J2 were placed per well of a 96-well plate in 95 ml of water. Treatments and control consisted of 5 mL of a DMSO-Tween solution (0.2% Tween 20 in DMSO) added to each well. The stock test solutions were prepared at 10 mg/ml resulting in an initial concentration of 0.5 mg/ml (except for compound 19 which was tested at 0.25 mg/ml due to solubility problems) and four replicates were used for each test. The nematicidal activity data are presented as percent dead J2 corrected according to Scheider-Orelli's formula. Five serial dilutions were used to calculate the effective lethal doses (LC₅₀ and LC₉₀) with Probit Analysis (STATGRAPHICS Centurion XVI, version 16.1.02).⁴⁷

In vitro Effects on Egg Hatching

Three egg masses of uniform size were washed with sterilized distilled water and transferred to a 12-well plate containing 400 μL of distilled water. Treatments and controls consisted of 22 mL of a DMSO-Tween solution (0.2% Tween 20 in DMSO, with or without the test compound) added to each well. Each experiment was replicated four times. The plates were covered to prevent evaporation and incubated in the darkness at 25 °C. After the incubation period (5 days), the hatched J2 s were counted, and the test solutions were replaced with sterilized distilled water. The egg masses were monitored weekly (immersion time).⁹ The number of hatched J2 was calculated after four immersion times. Values were transformed by Log10 (x+ 1), analyzed by ANOVA, and means separated by Least Significant Difference Test at P < .05. The relative suppression rate was calculated for each immersion time as follows:

Relative suppression rate (%)= (number of J2 in control—number of J2 in test solutions) / number of J2 in control× 100.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241227689 - Supplemental material for Potential of 2-Hydroxyacetophenone Derivatives and Simple Phenol's for the control of Meloidogyne javanica

Supplemental material, sj-docx-1-npx-10.1177_1934578X241227689 for Potential of 2-Hydroxyacetophenone Derivatives and Simple Phenol's for the control of Meloidogyne javanica by Luis Alberto González López, Maria Fe Andres, Wiston Quiñones, Fernando Echeverri and Azucena Gonzalez-Coloma in Natural Product Communications

Footnotes

Acknowledgements

We acknowledge Felipe de la Peña (ICA-CSIC) for technical support with nematicidal tests.

Author Contributions

LAG and AGC wrote the first draft of the manuscript and formatted the last version. AGC edited the manuscript. MFA, FE, and WQ revised the manuscript. LAG, FE, and WQ performed the chemical synthesis; MFA and AGC performed the biological experiments. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Data available upon request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical Approval is not applicable for this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has been supported by grants ICOOP-CSIC: COOPA20324L, Ministerio de Ciencia, Tecnología e Innovación Minciencias and Universidad de Antioquia, grant number 111571249860-061-2016, contract 061-2016A and grant PID2019-106222RB-C31/SRA (Agencia Española de Investigación AEI, 10.13039/501100011033). Minciencias and Universidad de Antioquia scholarship in Doctorados Nacionales Program, 647-2014 was granted to Luis Alberto González López.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

ORCID iDs

Luis Alberto González López

Azucena Gonzalez-Coloma

Supplemental Material

Supplemental material for this article is available online.

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