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Article

4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi

by
Elena R. Lopat’eva
1,
Alexander S. Budnikov
1,2,
Igor B. Krylov
1,2,3,*,
Anna L. Alekseenko
1,3,
Alexey I. Ilovaisky
1,2,
Alexey P. Glinushkin
2 and
Alexander O. Terent’ev
1,2,3,*
1
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, Russia
2
All-Russian Research Institute for Phytopathology, B. Vyazyomy, 143050 Moscow Region, Russia
3
Faculty of Chemical and Pharmaceutical Technology and Biomedical Products, D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, 125047 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Agrochemicals 2023, 2(1), 34-46; https://doi.org/10.3390/agrochemicals2010004
Submission received: 29 November 2022 / Revised: 17 December 2022 / Accepted: 3 January 2023 / Published: 9 January 2023
(This article belongs to the Section Fungicides and Bactericides)
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Abstract

:
The search for fungicides of novel classes is the long-standing priority in crop protection due to the continuous development of fungal resistance against currently used types of active compounds. Recently, 4-nitropyrazolin-3-ones were discovered as highly potent fungicides, of which activity was believed to be strongly associated with the presence of a nitro group in the pyrazolone ring. In this paper, a series of 4-substituted pyrazolin-3-ones were synthesized and their fungicidal activity against an important species of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum) was tested in vitro. We discovered that 4-mono and 4,4-dihalogenated pyrazolin-3-ones demonstrate fungicidal activity comparable to that of 4-nitropyrazolin-3-ones and other modern fungicides (such as kresoxim methyl). This discovery indicates that NO2 moiety can be replaced by other groups of comparable size and electronic properties without the loss of fungicidal activity and significantly expands the scope of potent new fungicides based on a pyrazolin-3-one fragment.

1. Introduction

In today’s world, the problem of microbial contamination of agricultural crops is critical to providing food for a growing human population [1]. Fungi represent one of the most harmful groups of phytopathogens, which account for up to 80% of crop losses [2,3,4,5]. Moreover, phytopathogenic fungi produce toxic metabolites, which represent a serious risk for public health as food contaminants [6,7,8,9]. Besides, fungal pathogens can cause opportunistic fungal infections in humans and animals [10,11].
Despite active research [12,13,14], the output of new fungicides has been relatively constant for the past 20 years [15]. To date, only a few classes of compounds dominate the market (77% of sales in 2018 [15]): Quinone outside Inhibitors (QoI, strobilurins, C3), De-Methylation Inhibitors (DMI, triazoles and imidazoles, G1) [16], Succinate-dehydrogenase inhibitors (SDHI, C2) [17], Dithiocarbamates (M03), Chloronitriles (M05), Carboxylic Acid Amides (CAA, H5) and Phenyl Amides (PA, A1), which has created the basis for the development of pest resistance [18]. In addition, the use of fungicides with the same mechanism of action both for agricultural needs and in medicine can create conditions for outbreaks of human diseases caused by ant. imycotic-resistant strains of fungi [19,20]. In this regard, the development of novel types of fungicides (First-in-Class compounds) is a necessary and urgent task [21].
The five-membered pyrazolin-3-one (pyrazolone) ring is a privileged structural motif in medicinal chemistry with a wide range of biological activities [22] (Figure 1). The practical importance of pyrazolones attracts continuous interest to the development of their synthetic methodology and properties [23,24]. The history of the medical use of 4-unsubstituted pyrazolinones began as early as 1887 with the discovery of antipyrine (1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one), one of the first nonopioid analgesics and antipyretics. This discovery prompted the study of pyrazolone derivatives, including C4-monosubstituted pyrazolones, pyrazolone-based Schiff bases, and their metal complexes, which possess anti-inflammatory, antipyretic and analgesic [22,25,26,27], antitumor/cytotoxic [22,25,28,29,30], antimicrobial [22,25,31,32,33], antioxidant [22,26], and protein denaturation inhibiting [27] activities. The interest of medicinal chemists to pyrazolones has been maintained and is increasing at the present time [22]. Recently, C4-disubstituted pyrazolones, primarily spiropyrazolones, have also attracted increasing attention as biologically active compounds [34,35,36]. Due to the wide spectrum of the biological activity of disubstituted pyrazolones, new asymmetric methods for their synthesis are being actively developed [36,37,38,39,40,41]. C4-disubstituted pyrazolones are recognized as valuable antitumor agents [35,42,43,44,45,46], antimicrobial substances [47], inhibitors of trypanosomal phosphodiesterase B1 [48], RalA inhibitors [49], and miticides [50]. However, their potential as effective fungicides has not been expected.
In our previous reports, 4-nitropyrazoline-3-ones were discovered as the novel class of highly potent broad spectrum fungicides [51,52]. However, the understanding of the underlying modes of action was lacking. To shed light on this issue, it is desirable to know how the structure of pyrazolone derivatives affects their fungicidal activity. Our previous study [51] of the structure–activity relationship revealed the importance of the aromatic substituent at N2, a small alkyl substituents at the C4 and C5 atoms of the pyrazolone ring, and the C(sp3)-hybridized C4 atom for high fungicidal activity [51]. Since the unnitrated pyrazolone (1) did not exhibit significant activity [52] (Figure 1), fungicidal properties were believed to be associated with the presence of a nitro group in the pyrazolone ring. In the present work, we aimed to synthesize and study other pyrazolones with a C(sp3)-hybridized C4 atom containing no nitro-group to reveal the role of substituents at this position for the fungicidal activity.

2. Results and Discussion

2.1. The Synthesis of the 4,4-Disubstituted Pyrazolone Derivatives

We have synthesized and tested a series of pyrazolones with variable substituent at position 4 instead of the NO2 group to reveal the role of this substituent. The structure of one of the most active nitropyrazolones, 4,5-dimethyl-4-nitro-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1a, Scheme 1), was used as the reference [51,52].
Synthetic approaches to the target compounds 1b–1j and 2d–g are shown in Scheme 1. A previously developed synthetic procedure using N2O4 as a nitrating agent [51] was used for the synthesis of 1a. The advantages of this method are the absence of metal-containing reagents in contrast to the metal salt/NaNO2 system [52], high selectivity, and scalability up to multigram quantities without the yield drop and without the need for chromatographic purification of the target product. 4-Methyl-4-hydroxypyrazolone (1b) was synthesized by aerobic oxidation of 4-methyl-2-phenyl-5-dimethyl-pyrazolin-3-one (1) under basic conditions (K2CO3) [53]. The further methylation step gave 4-methoxypyrazolone (1c). Monohalogenated fluoro-, chloro- and bromopyrazolones (1d–f) were synthesized by the halogenation of pyrazolone 1 with Selectfluor™, N-chlorosuccinimide (NCS), and N-bromosuccinimide (NBS), respectively. It should be noted that these procedures provided up to quantitative yields. 4,4-Dihalogenated pyrazolones (2d–f) were synthesized similarly from 2-phenyl-5-dimethyl-pyrazol-3-one (2) employing two equivalents of halogenating agents. 4-Azido-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1g) was synthesized with nearly quantitative yield (99%) according to the modified literature procedure [54]. However, the same procedure was less effective for the synthesis of diazide (2g) from 2, where only 25% yield of 2g was obtained. Thiocyanate (1h) was synthesized according to the previously developed procedure for the thiocyanation of the CH-acidic substrates [55]. Dimers (1i and 1j) were synthesized by dehydrogenative dimerization of 1 employing mixed heterogeneous photocatalysis and homogeneous organocatalysis in photooxidative system N-hydroxyphthalimide (NHPI)/TiO2 [56]. The reaction proceeded under air as the terminal oxidant to obtain the mixture of diastereomeric dimers with a total yield of 84%.

2.2. Study of the Fungicidal Activity of 4,4-Disubstituted Pyrazolones

In the next step we tested the fungicidal activity of the synthesized 4-disubstituted 2-phenyl-5-methylpyrazolin-3-ones against six species of phytopathogenic fungi characterized by high impact on crop production: Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum. Tests were performed by using the mycelium radial growth inhibition method in Petri dishes at a concentration of 10 mg/L and 5 mg/L in the culture medium. Kresoxim-methyl and triadimefon were used as the reference compounds (Table 1).
The results of fungicidal tests showed that the nitro group in the fourth position of the pyrazolone ring is not the principal structural element responsible for the manifestation of fungicidal activity, as it was previously assumed [51,52]. The most effective derivatives were revealed: 4-methyl-4-chloropyrazolone (1e), 4-methyl-4-bromopyrazolone (1f), 4,4-dichloropyrazolone (2e), 4,4-dibromopyrazolone (2f) and 4,4-diazidopyrazolone (2g). Fluorinated derivatives (1d and 2d) were moderately active. Monoazide derivative (1g) and thiocyanate (1h) showed low activity. The least active are pyrazolones with hydroxy and methoxy substituents (1b and 1c), as well as dimeric compounds (1i and 1j).
It should be noted that the synthesized C4-disubstituted pyrazolones have a different spectrum of activity than kresoxim-methyl. Pyrazolones 1a, 1d, 1f, 2e, 2f and 2g are more active against F. moniliforme, and 4,4-dibromopyrazolone 2f also showed outstanding activity against S. sclerotiorum, the least affected by kresoxim-methyl, even at concentrations as low as 5 mg/L. Pyrazolones 1a, 1d, 1e, 2e, 2f and 2g showed activity at or above the kresoxim-methyl level against B. sorokiniana, with nitropyrazolone 1a being the most active on the list. Pyrazolones 1a, 1e, 1f, 2e, 2f and 2g have excellent activity against V. inaequalis and R. solani: up to 100% mycelium growth inhibition at a concentration of 10 mg/L or 5 mg/L in the case of dihalogen pyrazolones 2e and 2f. Thus, the newly discovered fungicidal compounds can serve as a useful addition to the current range of agricultural fungicides for the control of fungi that are the least susceptible to existing fungicides.
Most of the previously known biologically active C4-disubstituted pyrazolones, with the exception of TELIN [43], belong to the class of spiro compounds bearing two C—C bonds at C4. Thus, the main structural feature that distinguishes the pyrazolones tested by us from other biologically active C4-disubstituted pyrazolones is the presence of a C4-heteroatom bond, which may be a key aspect for the manifestation of fungicidal activity.

3. Materials and Methods

K2CO3 (98%, extra pure, anhydrous, Thermo Scientific, Waltham, MA, USA), CH3I (99.5%, Acros Organics, Geel, Belgium), Selectfluor (95%, Acros Organics), N-chlorosuccinimide (98%, Acros Organics), N-bromosuccinimide (99%, Acros Organics), NaN3 (99.5%, Acros Organics), I2 (99.8%, Acros Organics), NH4SCN (97.5%, Acros Organics), Ce(NH4)2(NO2)6 (CAN, 98.5%, Thermo Scientific), N-hydroxypthalimide (NHPI, 98%, Acros Organics) were used as is. Hombikat UV 100 (anatase, specific surface area, BET: 300 m2·g−1, primary crystal size according to Scherrer < 10 nm) was used as is. 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 [51] and 4,5-dimethyl-4-nitro-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1a [51] were synthesized according to the literature procedures. CH3CN was distilled over P2O5, acetone was distilled over KMnO4. 1,4-dioxane, DMSO, and glacial AcOH were used as is from commercial sources.
In all experiments, see Supplementary File, RT stands for 22–25 °C. 1H and 13C NMR spectra were recorded on a Bruker AVANCE II 300 and Bruker Fourier 300HD (300.13 and 75.47 MHz, respectively) spectrometers in CDCl3 and DMSO-D6. FT-IR spectra were recorded on Bruker Alpha instrument. High-resolution mass spectra (HR-MS) were measured on a Bruker maXis instrument using electrospray ionization (ESI). The measurements were performed in a positive ion mode (interface capillary voltage—4500 V); mass range from m/z 50 to m/z 3000 Da; external calibration with Electrospray Calibrant Solution (Fluka). A syringe injection was used for all acetonitrile solutions (flow rate 3 µL/min). Nitrogen was applied as a dry gas; the interface temperature was set at 180 °C.
For investigation of fungicidal activity, aseptic polystyrene Petri dishes (90 × 17 mm) were used. All glassware used for addition and mixing of acetone solutions of the tested compounds with agar medium were sterilized before usage. Experiments were performed in a laminar flow cabinet.

3.1. 4-Hydroxy-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1b [57]

4-Hydroxy-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1b was synthesized according to the literature procedure [53]. K2CO3 (20 mol.%, 0.4 mmol, 55 mg) was added to a solution of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (2 mmol, 376 mg) in dioxane (30 mL). Then the flask was evacuated and filled with oxygen three times. The reaction mixture was stirred at 35 °C; for 24 h. Then the solution was evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 3/1 to afford 1b as white crystals (377 mg, 1.85 mmol, 93%). Mp = 111–112 °C (lit. Mp = 113 °C [57]). 1H NMR (300.13 MHz, CDCl3): δ = 7.84 (m, 2H, ArH), 7.38 (m, 2H, ArH), 7.18 (m, 1H, ArH), 4.58 (bs, 1H, OH), 2.18 (s, 3H), 1.53 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 174.8, 163.4, 133.7, 129.0, 125.5, 119.0, 77.4, 22.3, 12.7.

3.2. 4-Methoxy-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1c

CH3I (1.5 mmol, 213 mg) was added to a stirred solution of 4-hydroxy-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1 (1 mmol, 204 mg) and K2CO3 (1.5 mmol, 207 mg) in acetone (10 mL). The reaction mixture was refluxed for 15 h, and the product formation was monitored by TLC (eluent Petroleum Ether/EtOAc = 5/1, Rf = 0.5). Then the reaction mixture was diluted with CH2Cl2 (20 mL) and water (20 mL), the CH2Cl2 layer was separated, and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). Then, all organic extracts were combined, washed with water (2 × 20 mL), and dried over MgSO4. The solvent was rotary evaporated and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 5/1 to afford 1c as a slightly yellow liquid (23 mg, 0.11 mmol, 11%). 1H NMR (300.13 MHz, CDCl3): δ = 7.92 (m, 2H), 7.41 (m, 2H), 7.20 (m, 1H), 3.20 (s, 3H), 2.15 (s, 3H), 1.47 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 171.6, 161.3, 137.9, 129.0, 125.4, 118.6, 82.8, 54.3, 20.7, 13.1. FT-IR (thin layer): νmax = 1596, 1500, 1398, 1364, 1304, 1241, 1136, 1058, 759, 693 cm−1. HR-MS (ESI): m/z = 236.1397, calcd. for C12H14N2O2+NH4+: 236.1394

3.3. 4-Fluoro-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1d

SelectfluorTM (177 mg, 0.5 mmol) was added to a solution of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (94 mg, 0.5 mmol) in CH3CN (5 mL) at 60 °C. The reaction mixture was stirred for 1.5 h at 60 °C, then diluted with water (20 mL) and CH2Cl2 (10 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with brine (20 mL), and dried over MgSO4. Then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the CH2Cl2 eluent to afford 1d as yellow liquid (92 mg, 89%). 1H NMR (300.13 MHz, CDCl3): δ = 7.94–7.80 (m, 2H), 7.46–7.34 (m, 2H), 7.25–7.14 (m, 1H), 2.19 (d, J = 1.6 Hz, 2H), 1.65 (d, J = 23.3 Hz, 2H). 13C NMR (75.47 MHz, CDCl3): δ = 168.2 (d, J = 21.5 Hz), 158.1 (d, J = 16.6 Hz), 137.4, 129.0, 125.5, 118.5, 92.1 (d, J = 191.0 Hz), 18.8 (d, J = 27.0 Hz), 12.66 (d, J = 1.2 Hz). 19F NMR (282.47 MHz, CDCl3): δ = −166.72 (q, J = 23.1 Hz). FT-IR (thin layer): νmax = 1736, 1598, 1501, 1368, 1144, 1117, 758. HR-MS (ESI): m/z = 229.0744, calcd. for C11H11FN2O+Na+: 229.0748

3.4. 4-Chloro-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1e [58]

The solution of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (1 mmol, 188 mg) in CH3CN (20 mL) was added to a solution of N-chlorosuccinimide (NCS, 1.1 mmol, 147 mg) in CH3CN (5 mL) dropwise in 5 min at room temperature. The reaction mixture was stirred for another 30 min, then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 5/1 to afford 1e as white crystals (218 mg, 0.98 mmol, 98%). Mp = 68–69 °C (lit. Mp = 68 °C [58]). 1H NMR (300.13 MHz, CDCl3): δ = 7.89 (m, 2H), 7.41 (m, 2H), 7.21 (m, 1H), 2.24 (s, 3H), 1.77 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 169.8, 159.5, 137.6, 129.1, 125.6, 118.9, 62.7, 22.5, 12.9.

3.5. 4-Bromo-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1f [58]

The solution of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (1 mmol, 188 mg) in CH3CN (20 mL) was added to a solution of N-bromosuccinimide (NBS, 1.1 mmol, 196 mg) in CH3CN (5 mL) dropwise in 5 min at room temperature. The reaction mixture was stirred for another 30 min, then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 10/1 to afford 1f (259 mg, 0.97 mmol, 97%) as yellow crystals. Mp = 81–82 °C (lit. Mp = 83 °C [58]). 1H NMR (300 MHz, Chloroform-d) δ 7.93–7.86 (m, 2H), 7.45–7.37 (m, 2H), 7.25–7.17 (m, 1H), 2.29 (s, 3H), 1.87 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 170.3, 159.3, 137.7, 129.1, 125.6, 118.8, 52.7, 22.5, 13.2. FT-IR (thin layer): νmax = 1716, 1621, 1594, 1442, 1397, 1366, 1304, 1129, 767, 696, 635, 574, 511 cm−1. HR-MS (ESI): m/z = 268.0515, calcd. for C11H11BrN2O + H: 268.0506.

3.6. 4,4-Difluoro-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2d [59]

Selectfluor (354 mg, 1 mmol) was added to a solution of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2 (0.5 mmol, 87 mg) in CH3CN (5 mL) under heating (60 °C). The reaction mixture was stirred at 60 °C for 30 min. Then the reaction mixture was diluted with water (20 mL) and CH2Cl2 (10 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with brine (20 mL), and dried over MgSO4. Then the solvent was rotary evaporated to afford 2d as a yellow liquid (93 mg, 88%). 1H NMR (300.13 MHz, CDCl3): δ = 7.87–7.68 (m, 2H), 7.44–7.30 (m, 2H), 7.25–7.15 (m, 1H), 2.23 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 159.2 (t, J = 29.9 Hz), 152.0 (t, J = 23.0 Hz), 136.8, 129.2, 126.3, 118.6, 108.2 (t, J = 256.6 Hz), 11.8. 19F NMR (282.39 MHz, CDCl3): δ = -123.1. FT-IR (thin layer): νmax = 1751, 1597, 1501, 1255, 1148, 1114, 756. HR-MS (ESI): m/z = 211.0684, calcd. for C10H8F2N2O + H+: 211.0677.

3.7. 4,4-Dichloro-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2e [60]

N-chlorosuccinimide (NCS, 2 mmol, 267 mg) was added in portions to a solution of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2 (1 mmol, 174 mg) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 30 min, then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the CH2Cl2 eluent to afford 2e as yellow crystals (185 mg, 0.76 mmol, 76%). Mp = 61–62 °C (lit. Mp = 61.5–63°C [60]). 1H NMR (300.13 MHz, CDCl3): δ = 7.93–7.81 (m, 2H), 7.52–7.41 (m, 2H), 7.33–7.20 (m, 1H), 2.39 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 164.1, 155.6, 137.0, 129.2, 126.3, 119.0, 73.5, 12.2. FT-IR (thin layer): νmax = cm−1. HR-MS (ESI): m/z = 243.0085, calcd. for C10H11Cl2N2O + H+: 243.0086.

3.8. 4,4-Dibromo-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2f [61]

N-bromosuccinimide (NBS, 2 mmol, 356 mg) was added in portions to a solution of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2 (1 mmol, 174 mg) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 30 min, then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using eluent Petroleum Ether/EtOAc = 10/1 to afford 2f as yellow crystals (297 mg, 0.89 mmol, 89%). Mp = 76–78 °C (lit. Mp = 80–82 °C [61]). 1H NMR (300.13 MHz, CDCl3): δ = 7.93–7.82 (m, 2H), 7.49–7.36 (m, 2H), 7.33–7.19 (m, 1H), 2.44 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 165.3, 156.1, 137.1, 129.2, 126.2, 119.0, 46.2, 13.3. FT-IR (thin layer): νmax = 1722, 1592, 1491, 1364, 1283, 948, 804, 765, 694, 659, 632, 510 cm−1. HR-MS (ESI): m/z = 330.9068, calcd. for C10H8Br2N2O + H: 330.9076.

3.9. 4-Azido-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1g

4-azido-4,5-dimethyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 1g was synthesized according to the modified literature procedure [54]. I2 (1.1 mmol, 279 mg) was added to a suspension of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (1 mmol, 188 mg) and NaN3 (3 mmol, 195 mg) in DMSO (10 mL). The reaction mixture was stirred at room temperature, and the formation of the product was monitored by TLC (eluent Petroleum Ether/EtOAc = 5/1, Rf = 0.6). Then the reaction mixture was diluted with Na2S2O3 solution (0.1 M, 30 mL) and CH2Cl2 (10 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with water (2 × 20 mL), and dried over MgSO4. Then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 5/1 to afford 1g as a colorless liquid (226 mg, 0.99 mmol, 99%). 1H NMR (300.13 MHz, CDCl3): δ = 7.88 (m, 2H), 7.41 (m, 2H), 7.21 (m, 1H), 2.14 (s, 3H), 1.63 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 170.7, 159.6, 137.6, 129.1, 125.6, 118.8, 66.0, 18.7, 13.2. FT-IR (thin layer): νmax = 2109, 1719, 1597, 1501, 1399, 1366, 1312, 1246, 1137, 756, 692 cm−1. HR-MS (ESI): m/z = 252.0860, calcd. for C11H11N5O+Na+: 252.0856.

3.10. 4,4-Diazido-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2g [54]

4,4-diazido-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2g was synthesized according to the literature procedure [54]. I2 (2.2 mmol, 558 mg) was added to a suspension of 5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2 (1 mmol, 174 mg) and NaN3 (6 mmol, 390 mg) in DMSO (10 mL). The reaction mixture was stirred at room temperature, and the formation of the product was monitored by TLC (eluent Petroleum Ether/EtOAc = 20/1, Rf = 0.5). Then the reaction mixture was diluted with Na2S2O3 solution (0.1 M, 30 mL) and CH2Cl2 (10 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with water (2 × 20 mL), and dried over MgSO4. Then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 20/1 to afford 2g as brown liquid (62 mg, 0.25 mmol, 25%). 1H NMR (300 MHz, Chloroform-d) δ 7.96–7.85 (m, 2H), 7.53–7.39 (m, 2H), 7.34–7.21 (m, 1H), 2.18 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 163.9, 155.6, 136.8, 129.2, 126.2, 118.8, 13.0.

3.11. 4,5-Dimethyl-2-phenyl-4-thiocyanato-2,4-dihydro-3H-pyrazol-3-one 1h [55]

4,5-dimethyl-2-phenyl-4-thiocyanato-2,4-dihydro-3H-pyrazol-3-one 1h was synthesized according to the literature procedure [55]. Ce(NH4)2(NO2)6 (CAN, 3 mmol, 1644 mg) was added in portions to a solution of 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (1 mmol, 188 mg) and NH4SCN (3 mmol, 228 mg) in AcOH (10 mL) within 30 min. The reaction mixture was stirred at room temperature, and the formation of the product was monitored by TLC (eluent Petroleum Ether/EtOAc = 5/1). Then the reaction mixture was diluted with CH2Cl2 (20 mL) and water (20 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with water (2 × 20 mL), and dried over MgSO4. Then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent Petroleum Ether/EtOAc = 5/1 to afford 1h as slightly yellow crystals (97 mg, 0.40 mmol, 40%). Mp = 99–100 °C (lit. Mp = 97–99 °C [55]). 1H NMR (300.13 MHz, CDCl3): δ = 7.92 (m, 2H), 7.48 (m, 2H), 7.29 (m 1H), 2.35 (s, 3H), 1.76 (s, 3H). 13C NMR (75.47 MHz, CDCl3): δ = 169.4, 157.6, 137.1, 129.1, 126.1, 119.3, 107.2, 56.8, 18.7, 13.4. FT-IR (thin layer): νmax = cm−1. HR-MS (ESI): m/z = 268.0506, calcd. for C12H11N3OS+Na+: 268.0515.

3.12. 4,4’,5,5’-Tetramethyl-2,2’-diphenyl-2,2’,4,4’-tetrahydro-3H,3’H-[4,4’-bipyrazole]-3,3’-dione, meso 1i and racemic 1j [62]

Dimers were synthesized according to the modified literature procedure [56]. To a 50 mL round-bottomed flask 4,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 1 (1 mmol, 188 mg), TiO2 Hombikat UV 100 (20 mg), N-hydroxyphthalimide (20 mol%, 0.2 mmol, 32.6 mg) and a solvent (CH3CN, 2 mL) were placed. The resulting suspension was sonicated for 1 min. The stirred reaction mixture was irradiated with 10 W Blue LED (443 nm) at room temperature until full conversion of 1 (2 h, monitored by TLC, eluent CH2Cl2). Upon completion, the reaction mixture was diluted with CH2Cl2 (20 mL) and water (20 mL). The CH2Cl2 layer was separated and the water layer was additionally extracted with CH2Cl2 (2 × 10 mL). All organic extracts were combined, washed with NaHCO3 saturated solution (20 mL) and water (20 mL), and dried over MgSO4. Then the solvent was rotary evaporated, and the residue was purified by column chromatography on silica gel using the eluent CH2Cl2/EtOAc = 40/1 to afford diastereomeric dimers 1i (54%, 0.27 mmol, 100 mg) and 1j (30%, 0.15 mmol, 56 mg) as white crystals.
Meso-3,3’,4,4’-tetramethyl-1,1’-diphenyl-[4,4’-bipyrazol]-5,5’-dione, 1i Mp = 161–162 °C (Lit. Mp = 163–164 °C [62]); 1H NMR (300.13 MHz, CDCl3): δ = 7.93–7.87 (m, 2H), 7.46–7.38 (m, J = 10.8, 5.1 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 1.93 (s, 6H), 1.73 (s, 6H); 13C NMR (75.47 MHz, CDCl3): δ = 173.1, 161.9, 137.6, 129.1, 125.7, 119.0, 54.4, 14.7, 14.6.
Racemic-3,3’,4,4’-tetramethyl-1,1’-diphenyl-[4,4’-bipyrazol]-5,5’-dione, 1j Mp = 141–142 °C (Lit. Mp = 140–141 °C [62]); 1H NMR (300.13 MHz, CDCl3): δ = 7.85 (d, J = 7.9 Hz, 4H), 7.45–7.31 (m, 4H), 7.18 (t, J = 7.3 Hz, 2H), 2.19 (s, 6H), 1.60 (s, 6H); 13C NMR (75.47 MHz, CDCl3): δ = 173.1, 159.8, 137.7, 129.0, 125.4, 119.3, 55.7, 16.0, 15.4.

3.13. Investigation of Fungicidal Activity (Table 1)

The fungicidal activity was investigated according to a standard procedure [63,64,65,66,67,68,69]. The strains for fungicidal studies were obtained from the working collection of the All-Russian Research Institute for Phytopathology (B. Vyazemy, Moscow reg., Russia): Venturia inaequalis (V.i.) MRA-16-2, Rhizoctonia solani (R.s.) 100063, Fusarium oxysporum (F.o.) FO-8, Fusarium moniliforme (F.m.) 100146, Bipolaris sorokiniana (B.s.) MRB(V)-1, Sclerotinia sclerotiorum (S.s.) 100033. The test substances preliminarily dissolved in acetone (concentration 1 or 0.5 mg mL−1) were introduced into liquid potato sugar agar having a temperature of 50–55 °C so that the final concentration of the substance in the nutrient medium was 10 mg L−1 or 5 mg L−1 (0.9 mL of solution in acetone per 90 mL of agar). After mixing, the agar was poured into sterile Petri dishes and cooled to room temperature. Pieces of mycelium from the peripheral growth zone of mycelium culture incubated for 3–5 days were transferred to Petri dishes with diluted tested compounds using a needle. The control was a colony grown in the same nutrient medium without the addition of the active substance (acetone without substance was added). After inoculation for 72 h, the diameters of the formed fungal colonies were measured. The indicator of fungicidal activity was the suppression of mycelium growth in comparison with the control, calculated as [(Dc−Ds)/Dc] × 100 %, in which Dc is the diameter of the colony of fungus in the control medium and Ds is the diameter of the colony in the medium with the test substance added.

4. Conclusions

Pronounced broad spectrum fungicidal activity was found to be characteristic for a wide range of C4-disubstituted pyrazolin-3-ones. This discovery shows that 4-nitropyrazolin-3-ones, previously reported as a novel class of fungicides, are actually the subgroup of a more diverse type of fungicidal structures, which can be explored further. Currently, the most active compounds are 4,4-dichloro-, 4,4-dibromo pyrazolin-3-ones 2e and 2f. 4-Methyl-4-chloro-, 4-methyl-4-bromo- and 4,4-diazidopyrazolones showed somewhat lower activity. For the most active structures, efficient synthesis procedures have been proposed that allow for obtaining substances with high to quantitative yields. The ease of synthesis, the availability of reagents, and high fungicidal activity comparable to that of commercial fungicides, make the discovered 4-disubstituted pyrazolin-3-ones attractive candidates for the role of a new class of fungicidal compounds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/agrochemicals2010004/s1, 1H and 13C NMR spectra of the synthesized compounds, FT-IR and HRMS data for new compounds.

Author Contributions

Conceptualization, I.B.K. and A.O.T.; investigation, E.R.L., A.S.B., A.L.A. and I.B.K.; writing—original draft preparation, E.R.L.; writing—review and editing, I.B.K., A.S.B. and A.O.T.; supervision, A.I.I., A.P.G. and A.O.T.; project administration, A.I.I. and A.P.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Russian Science Foundation, grant number 19-73-20190.

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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Agrochemicals 02 00004 g001 550
Figure 1. Selected examples of biologically active C4-disubtituted pyrazolin-3-ones.
Figure 1. Selected examples of biologically active C4-disubtituted pyrazolin-3-ones.
Agrochemicals 02 00004 g001
Agrochemicals 02 00004 sch001 550
Scheme 1. Synthetic approaches to 4-substituted pyrazolin-3-ones used in the present study.
Scheme 1. Synthetic approaches to 4-substituted pyrazolin-3-ones used in the present study.
Agrochemicals 02 00004 sch001
Table
Table 1. In vitro fungicidal activity of the 4-substituted pyrazolin-3-ones *.
Table 1. In vitro fungicidal activity of the 4-substituted pyrazolin-3-ones *.
CompoundC, mg/LMycelium Growth Inhibition
V. i.R. s.F. o.F. m.B. s.S. s.
1Agrochemicals 02 00004 i001101001006110010088
2Agrochemicals 02 00004 i0021072011800
3Agrochemicals 02 00004 i003101125617114
4Agrochemicals 02 00004 i00410585180897442
5Agrochemicals 02 00004 i0051010010055616636
6Agrochemicals 02 00004 i0061010010031836054
7Agrochemicals 02 00004 i00710293253685336
8Agrochemicals 02 00004 i008101001008510077100
5100100681005231
9Agrochemicals 02 00004 i00910100100100100100100
51001009710062100
10Agrochemicals 02 00004 i01010333882261
11Agrochemicals 02 00004 i0111010010050837428
12Agrochemicals 02 00004 i01210223911111611
13Agrochemicals 02 00004 i0131011261711120
14Agrochemicals 02 00004 i014101124619140
15Kresoxim-methyl1010010065645854
16Triadimefon10495862826463
* Abbreviations used: V.i.—Venturia inaequalis, R.s.—Rhizoctonia solani, F.o.—Fusarium oxysporum, F.m.—Fusarium moniliforme, B.s.—Bipolaris sorokiniana, S.s.—Sclerotinia sclerotiorum. Fungicidal activity exceeding the standard (kresoxim-methyl) is highlighted.
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MDPI and ACS Style

Lopat’eva, E.R.; Budnikov, A.S.; Krylov, I.B.; Alekseenko, A.L.; Ilovaisky, A.I.; Glinushkin, A.P.; Terent’ev, A.O. 4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi. Agrochemicals 2023, 2, 34-46. https://doi.org/10.3390/agrochemicals2010004

AMA Style

Lopat’eva ER, Budnikov AS, Krylov IB, Alekseenko AL, Ilovaisky AI, Glinushkin AP, Terent’ev AO. 4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi. Agrochemicals. 2023; 2(1):34-46. https://doi.org/10.3390/agrochemicals2010004

Chicago/Turabian Style

Lopat’eva, Elena R., Alexander S. Budnikov, Igor B. Krylov, Anna L. Alekseenko, Alexey I. Ilovaisky, Alexey P. Glinushkin, and Alexander O. Terent’ev. 2023. "4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi" Agrochemicals 2, no. 1: 34-46. https://doi.org/10.3390/agrochemicals2010004

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