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Article

Synthesis, Structural Determination, and Antifungal Activity of Novel Fluorinated Quinoline Analogs

by
Xinpeng Sun
1,2,
Wei Yu
1,2,
Lijing Min
3,
Liang Han
2,
Xuewen Hua
4,
Jianjun Shi
5,
Nabo Sun
1,* and
Xinghai Liu
2,*
1
College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China
2
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
3
Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, College of Life Science, Huzhou University, Huzhou 313000, China
4
College of Agriculture, Liaocheng University, Liaocheng 252000, China
5
College of Chemistry and Chemical Engineering, Huangshan University, Huangshan 245041, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(8), 3373; https://doi.org/10.3390/molecules28083373
Submission received: 24 March 2023 / Revised: 7 April 2023 / Accepted: 8 April 2023 / Published: 11 April 2023
(This article belongs to the Special Issue Advances in Novel Pesticide Discovery)
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Versions Notes

Abstract

:
A series of new fluorinated quinoline analogs were synthesized using Tebufloquin as the lead compound, 2-fluoroaniline, ethyl 2-methylacetoacetate, and substituted benzoic acid as raw materials. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. The compound 8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert-butyl)benzoate (2b) was further determined by X-ray single-crystal diffraction. The antifungal activity was tested at 50 μg/mL, and the bioassay results showed that these quinoline derivatives had good antifungal activity. Among them, compounds 2b, 2e, 2f, 2k, and 2n exhibited good activity (>80%) against S. sclerotiorum, and compound 2g displayed good activity (80.8%) against R. solani.

1. Introduction

Nitrogen-containing heterocycles are important skeletons in synthetic chemistry [1,2,3,4,5]. In the development of heterocyclic pesticides, quinoline compounds, as a class of heterocyclic compounds with a quinoline skeleton [6], can be easily modified in structure, and play an important role in the development of new pesticides. Quinoline compounds not only have good antifungal [7,8,9,10], herbicidal [11], and anti-insecticidal [12] activities, but also have anticancer [13,14], antimalarial [15,16,17], and antituberculosis [18,19] activities. Since Runge [20] first extracted quinoline from coal tar, many natural quinoline compounds were discovered.
Among the more than 1200 commercialized pesticides, 424 pesticides contain at least one fluorine atom [21]. After organic compounds are fluorinated, their physical and chemical properties such as lipophilicity, water solubility, and metabolic stability will undergo significant changes [22], due to that they [23,24] have the characteristics of small radius and large electronegativity. Therefore, many commercial medicines or pesticides heterocycles containing fluorine atoms were commercialized. For example (Figure 1), the fluoroquinoline fungicide Ipflufenoquin [25] was recently developed by Japan’s Soda Company. The Meiji Fruit Industry in Japan has developed the fungicide Tebufloquin [26], which has excellent control effects on rice blast, and the commercial antifungal Ciprofloxacin.
In our previous work [27,28,29,30,31], many compounds based on the natural quinoline structure were synthesized and showed good activity. In recent work [32], we found that in the 8-position quinoline ring added p-chlorophenoxy group, some compounds showed certain activity. As we continued our effort to develop high-efficiency and low-toxicity new quinoline-based fungicides, the natural quinoline structure was selected as key core, 8-position of quinoline ring was replaced by fluorine atom, and the 4-position of hydroxyl on the quinoline ring was esterified (Figure 2 [32]). All new quinoline compounds were characterized by 1H NMR, 13C NMR, and HRMS, and their antifungal activity was tested.

2. Results and Discussion

2.1. Synthesis and Spectra Analysis

The synthetic route of title fluorinated quinoline analogs is shown in Scheme 1. First, 2-fluorophenol was directly reacted with ethyl 2-methylacetoacetate under polyphosphoric acid (PPA) to give 2,3-dimethyl-4-hydroxyquinoline intermediate 1. The PPA was used as both a solvent and an acidic catalyst, and the reactants are directly one-step synthesis of quinoline rings. Then, intermediate 1 undergoes esterification with various substituted benzoic acids to generate the target compound. When EDC•HCl and DMAP are used as condensation agent, the solvent has a great influence on the yield of this reaction. It was found that using DMF as solvent can give higher yield than using dichloromethane (DCM) as solvent (Table 1).
The two CH3 protons are at 2.3 and 2.8 ppm, respectively. The protons of the benzene ring are assigned at 7~9 ppm. Taking compound 2b as an example, the protons of two methyl groups can be found at δ 2.32 ppm and δ 2.80 ppm as singlets in the 1H NMR, while in the 13C NMR data, they are found at 12.87 ppm and 24.37 ppm, respectively. The C=O was found at 163.73 ppm in the 13C NMR.

2.2. Structure Determination

A colorless crystal of 8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert-butyl)benzoate, 2b, suitable for X-ray diffraction study, was cultivated in the test tube from EtOH by self-volatilization. A crystal with dimensions of 0.36 mm × 0.28 mm × 0.18 mm was mounted on a Bruker APEX-II CCD diffractometer equipped with graphite-monochromatic MoKα radiation (λ = 0.71073 Å). The crystal structure was solved by direct methods with SHELXS-97 [33] and refined by full-matrix least-squares refinements based on F2 with SHELXL-97. All nonhydrogen atoms were refined anisotropically, and all hydrogen atoms were located in the calculated positions and refined with a riding model. The detailed crystal data are listed in Table 2.

2.3. Fungicidal Activity and SAR

The antifungal activities of compounds 2a–2p against ten phytopathogenic fungi are listed in Table 3. Generally, these compounds showed good antifungal activity. For example, compounds 2b(4-Bu), 2e(4-F), 2g(4-OMe) and 2p displayed moderate activity (40~60%) against A. solani. For the P. oryae, compounds 2b, 2d, 2f, and 2p also exhibited moderate activity (40~60%), which is the same as the A. solani. The inhibition rate of compound 2f against P. capsicum reached 58.1%, which was the same as that of the positive control Tebufloquin (58.1%). Compounds 2e and 2j were both 45% inhibitory to F. oxysporum, which is a little better than the positive control Tebufloquin (42.9%). Among these fungi, compounds 2b, 2e, 2f, 2k, and 2n possessed good activity (>80%) against S. sclerotiorum, which were higher than the positive control Tebufloquin (75.0%). Compounds 2b and 2d also had good activity (53.8%) against B. cinerea, which was a little lower than that of the positive control Tebufloquin (56.7%), but the activity of compound 2n (57.7%) was a little higher than that of the positive control Tebufloquin (56.7%). For the R. solani, compounds 2g (80.8%) and 2p (76.9%) exhibited good activity, which were higher than the positive control Tebufloquin (69.7%). The inhibition rates of compounds 2b, 2f, and 2n against C. arachidicola were 46.7%, 46.7%, and 60%, respectively, which were higher than the positive control Tebufloquin (37.5%). The inhibitory rates of compounds 2e, 2f, 2k, and 2n, against P. piricola were 72.0%, 76.0%, 76.0%, and 76.0%, respectively, which were also higher than the positive control Tebufloquin (65.4%). Notably, all the title compounds had lower inhibition rates against G. zeae; only compounds 2b and 2n exceeded 30%. From Table 3, it can be concluded that substitution on the benzene ring can influence the activity. The 4-position of the benzene ring had an electron-given group with better activity, such as compounds 2b(4-Bu), 2g(4-MeO), 2j(4-Me), and 2n(4-i-Pr), while the 4-position of the benzene ring had an electron-withdraw group, which had low activity, except for compound 2e(4-F), which may be the influence of the fluorine atom. When the R was an alkyl group, such as compound 2p (cyclopropyl group), it also exhibited good activity.

3. Materials and Methods

3.1. Instruments

Melting points were determined using an X-4 apparatus and uncorrected. 1H NMR and 13C NMR spectra were measured on a Bruker AC-P500 and AC-P400 instrument using TMS as an internal standard and deuterated chloroform, CDCl3, as the solvent. HR-ESI-MS was tested using an Agilent 1100 HPLC-JEOL AccuTOF instrument. All reagents were of analytical grade or were freshly prepared before use.

3.2. Synthesis

3.2.1. Synthesis of Intermediate 1

The synthetic route is shown in Scheme 1. In a 250 mL three-necked flask, 2-fluoroaniline (11.11 g, 100.00 mmol), ethyl 2-methylacetoacetate (14.42 g, 100.00 mmol), and polyphosphoric acid (50.69 g, 150.00 mmol) were added, and the mixture was heated at 150 °C. After the reaction was completed, the mixture was cooled to room temperature. The three-necked flask was placed in an ice bath, and the pH was adjusted to 7–8 by 10% aqueous sodium hydroxide solution. Then, it was filtered and dried to give 8-fluoro-2,3-dimethylquinolin-4-ol (intermediate 1), white solid with the yield of 89.2%, mp 230–231 °C. 1H NMR (500 MHz, DMSO-d6) δ: 11.36 (s, 1H, OH), 7.88 (d, J = 8.1 Hz, 1H, Ph), 7.52–7.46 (m, 1H, Ph), 7.26–7.19 (m, 1H, Ph), 2.43 (s, 3H, CH3), 1.98 (s, 3H, CH3).

3.2.2. Synthesis of Target Compounds 2

The synthetic route is shown in Scheme 1. In a 50 mL round-bottomed flask, intermediate 1 (0.20 g, 1.05 mmol), substituted benzoic acid (1.16 mmol), EDC•HCl (0.24 g, 1.26 mmol), 4-dimethylaminopyridine (DMAP) (0.13 g, 1.05 mmol), and DMF (10 mL) were stirred at room temperature. After the reaction was completed, water (30 mL) was added, it was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain the target compounds 2a–2p.
8-fluoro-2,3-dimethylquinolin-4-yl benzoate (2a). White solid, yield 56.1%, mp 176~178 °C; 1H NMR (500 MHz, CDCl3) δ: 8.36–8.30 (m, 2H, Ph), 7.80–7.69 (m, 1H, Ph), 7.60 (t, J = 7.8 Hz, 2H, Ph), 7.56–7.49 (m, 1H, Ph), 7.42–7.29 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.33 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.75, 160.83, 157.74 (d, J = 255.8 Hz), 151.72 (d, J = 4.5 Hz), 137.55 (d, J = 12.2 Hz), 134.38, 130.49 (2C), 128.97 (2C), 128.21, 125.99 (d, J = 8.2 Hz), 123.58 (d, J = 2.4 Hz), 123.23, 116.72 (d, J = 4.7 Hz), 113.24 (d, J = 19.2 Hz), 24.39, 12.89; HRMS (ESI) for C18H14FNO2 m/z: Calculated, 296.1081, found, 296.1087 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert-butyl)benzoate (2b). White solid, yield 59.3%, mp 171~173 °C; 1H NMR (500 MHz, CDCl3) δ: 8.29–8.19 (m, 2H, Ph), 7.61 (d, J = 8.6 Hz, 2H, Ph), 7.56–7.50 (m, 1H, Ph), 7.40–7.30 (m, 2H, Ph), 2.80 (s, 3H, CH3), 2.32 (s, 3H, CH3), 1.41 (s, 9H, C(CH3)3); 13C NMR (151 MHz, CDCl3) δ: 163.73, 160.82, 158.37, 157. 73 (d, J = 256.7 Hz), 151.82 (d, J = 4.5 Hz), 137.52 (d, J = 12.1 Hz), 130.44 (2C), 125.97 (2C), 125.91 (d, J = 8.2 Hz), 125.38, 123.68 (d, J = 2.3 Hz), 123.28, 116.79 (d, J = 4.7 Hz), 113.18 (d, J = 19.2 Hz), 35.35, 31.11 (3C), 24.37, 12.87; HRMS (ESI) for C22H22FNO2 m/z: Calculated, 352.1707, found, 352.1713 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 2-fluorobenzoate (2c). White solid, yield 67.2%, mp 144~146 °C; 1H NMR (500 MHz, CDCl3) δ: 8.24–8.17 (m, 1H, Ph), 7.75–7.67 (m, 1H, Ph), 7.58 (d, J = 8.1 Hz, 1H, Ph), 7.44–7.28 (m, 4H, Ph), 2.81 (s, 3H, CH3), 2.35 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 162.54 (d, J = 262.0 Hz), 161.43 (d, J = 4.0 Hz), 160.87, 157.70 (d, J = 255.9 Hz), 151.46 (d, J = 4.6 Hz), 137.50 (d, J = 12.2 Hz), 136.04 (d, J = 9.1 Hz), 132.80, 126.11 (d, J = 8.2 Hz), 124.55 (d, J = 3.9 Hz), 123.39 (d, J = 2.4 Hz), 123.18, 117.53 (d, J = 22.1 Hz), 116.89 (d, J = 9.7 Hz), 116.75 (d, J = 4.7 Hz), 113.32 (d, J = 19.2 Hz), 24.32, 12.96; HRMS (ESI) for C18H13F2NO2 m/z: Calculated, 314.0987, found, 314.0993 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 3-fluorobenzoate (2d). White solid, yield 66.2%, mp 146~148 °C; 1H NMR (500 MHz, CDCl3) δ: 8.17–8.09 (m, 1H, Ph), 8.03–7.97 (m, 1H, Ph), 7.63–7.56 (m, 1H, Ph), 7.54–7.49 (m, 1H, Ph), 7.48–7.42 (m, 1H, Ph), 7.42–7.33 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 162.80 (d, J = 249.2 Hz), 162.65 (d, J = 3.1 Hz), 160.88, 157.75 (d, J = 256.1 Hz), 151.48 (d, J = 4.4 Hz), 137.53 (d, J = 12.1 Hz), 130.73 (d, J = 7.8 Hz), 130.29 (d, J = 7.5 Hz), 126.25 (d, J = 3.1 Hz), 126.15 (d, J = 8.2 Hz), 123.36 (d, J = 2.3 Hz), 123.16, 121.56 (d, J = 21.3 Hz), 117.35 (d, J = 23.3 Hz), 116.54 (d, J = 4.7 Hz), 113.37 (d, J = 19.2 Hz), 24.34, 12.90; HRMS (ESI) for C18H13F2NO2 m/z: Calculated, 314.0987, found, 314.0993 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-fluorobenzoate (2e). White solid, yield 48.5%, mp 152~154 °C; 1H NMR (500 MHz, CDCl3) δ: 8.48–8.22 (m, 2H, Ph), 7.55–7.46 (m, 1H, Ph), 7.41–7.32 (m, 2H, Ph), 7.31–7.25 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 166.65 (d, J = 256.6 Hz), 162.78, 160.88, 157.73 (d, J = 256.0 Hz), 151.60 (d, J = 4.5 Hz), 137.50 (d, J = 12.2 Hz), 133.19 (d, J = 9.6 Hz, 2C), 126.09 (d, J = 8.2 Hz), 124.43 (d, J = 3.0 Hz), 123.50 (d, J = 2.5 Hz), 123.24, 116.60 (d, J = 4.7 Hz), 116.29 (d, J = 22.2 Hz, 2C), 113.33 (d, J = 19.2 Hz), 24.31, 12.89; HRMS (ESI) for C18H13F2NO2 m/z: Calculated, 314.0987, found, 314.0993 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 2-methoxybenzoate (2f). White solid; yield 51.3%; mp 129~130 °C; 1H NMR (500 MHz, CDCl3) δ: 8.15 (dd, J = 7.9, 1.6 Hz, 1H, Ph), 7.69–7.61 (m, 2H, Ph), 7.44–7.30 (m, 2H, Ph), 7.17–7.09 (m, 2H, Ph), 3.99 (s, 3H, OCH3), 2.80 (s, 3H, CH3), 2.36 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.20, 160.81, 160.16, 157.70 (d, J = 255.5 Hz), 151.88 (d, J = 4.5 Hz), 137.54 (d, J = 12.1 Hz), 135.08, 132.52, 125.85 (d, J = 8.2 Hz), 123.76 (d, J = 2.5 Hz), 123.29, 120.50, 117.93, 117.10 (d, J = 4.6 Hz), 113.10 (d, J = 19.2 Hz), 112.36, 56.04, 24.40, 12.94; HRMS (ESI) for C19H16FNO3 m/z: Calculated, 326.1187, found, 326.1192 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-methoxybenzoate (2g). White solid, yield 57.3%, mp 86~88 °C; 1H NMR (500 MHz, CDCl3) δ: 8.35–8.20 (m, 2H, Ph), 7.55–7.50 (m, 1H, Ph), 7.40–7.30 (m, 2H, Ph), 7.09–7.03 (m, 2H, Ph), 3.94 (s, 3H, OCH3), 2.80 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.48, 162.31, 160.83, 157.73 (d, J = 255.7 Hz), 151.87 (d, J = 4.6 Hz), 137.52 (d, J = 12.0 Hz), 132.84 (2C), 125.89 (d, J = 8.2 Hz), 123.78 (d, J = 2.4 Hz), 123.32, 120.40, 116.82 (d, J = 4.7 Hz), 114.15 (2C), 113.17 (d, J = 19.2 Hz), 55.60, 24.38, 12.89; HRMS (ESI) for C19H16FNO3 m/z: Calculated, 326.1187, found, 326.1192 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 2-methylbenzoate (2h). White solid, yield 60.5%, mp 150~152 °C; 1H NMR (500 MHz, CDCl3) δ: 8.39 (d, J = 7.8 Hz, 1H, Ph), 7.64–7.50 (m, 2H, Ph), 7.48–7.31 (m, 4H, Ph), 2.81 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.34 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 164.03, 160.83, 157.76 (d, J = 255.8 Hz), 151.80 (d, J = 4.5 Hz), 142.34, 137.55 (d, J = 12.1 Hz), 133.58, 132.41, 131.47, 126.99, 126.30, 125.98 (d, J = 8.2 Hz), 123.72 (d, J = 2.4 Hz), 123.25, 116.76 (d, J = 4.7 Hz), 113.21 (d, J = 19.2 Hz), 24.37, 22.10, 12.95; HRMS (ESI) for C19H16FNO2 m/z: Calculated, 310.1238, found, 310.1243 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 3-methylbenzoate (2i). White solid, yield 63.1%, mp 126~128 °C; 1H NMR (500 MHz, CDCl3) δ: 8.17–8.07 (m, 2H, Ph), 7.58–7.51 (m, 2H, Ph), 7.48 (t, J = 7.9 Hz, 1H, Ph), 7.41–7.32 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.92, 160.85, 157.72 (d, J = 255.8 Hz), 151.80 (d, J = 4.5 Hz), 138.93, 137.51 (d, J = 12.2 Hz), 135.16, 130.97, 128.86, 128.12, 127.65, 125.97 (d, J = 8.2 Hz), 123.62 (d, J = 2.4 Hz), 123.26, 116.76 (d, J = 4.6 Hz), 113.24 (d, J = 19.2 Hz), 24.34, 21.34, 12.89; HRMS (ESI) for C19H16FNO2 m/z: Calculated, 310.1238, found, 310.1243 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-methylbenzoate (2j). White solid, yield 66.5%, mp 122~124 °C; 1H NMR (500 MHz, CDCl3) δ: 8.21 (d, J = 8.2 Hz, 2H, Ph), 7.56–7.50 (m, 1H, Ph), 7.43–7.30 (m, 4H, Ph), 2.80 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.81, 160.84, 157.73 (d, J = 255.7 Hz), 151.82 (d, J = 4.5 Hz), 145.43, 137.51 (d, J = 12.2 Hz), 130.55 (2C), 129.68 (2C), 125.94 (d, J = 8.2 Hz), 125.43, 123.68 (d, J = 2.4 Hz), 123.29, 116.78 (d, J = 4.7 Hz), 113.21 (d, J = 19.2 Hz), 24.35, 21.87, 12.88; HRMS (ESI) for C19H16FNO2 m/z: Calculated, 310.1238, found, 310.1243 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 2-chlorobenzoate (2k). White solid, yield 46.3%, mp 116~118 °C; 1H NMR (500 MHz, CDCl3) δ: 8.25 (dd, J = 7.8, 1.2 Hz, 1H, Ph), 7.66–7.56 (m, 3H, Ph), 7.51–7.47 (m, 1H, Ph), 7.44–7.39 (m, 1H, Ph), 7.39–7.34 (m, 1H, Ph), 2.82 (s, 3H, CH3), 2.37 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 162.43, 160.84, 157.71 (d, J = 255.7 Hz), 151.44 (d, J = 3.5 Hz), 137.53 (d, J = 11.9 Hz), 134.94, 134.03, 132.34, 131.81, 127.87, 127.07, 126.14 (d, J = 8.0 Hz), 123.37 (d, J = 2.6 Hz), 123.17, 116.74 (d, J = 4.0 Hz), 113.31 (d, J = 19.1 Hz), 24.35, 13.05; HRMS (ESI) for C18H13ClFNO2 m/z: Calculated, 330.0692, found, 330.0697 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 3-chlorobenzoate (2l). White solid, yield 68.5%, mp 148~150 °C; 1H NMR (500 MHz, CDCl3) δ: 8.30 (t, J = 1.7 Hz, 1H, Ph), 8.24–8.16 (m, 1H, Ph), 7.74–7.68 (m, 1H, Ph), 7.57–7.48 (m, 2H, Ph), 7.42–7.34 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.32 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 162.59, 160.88, 157.74 (d, J = 256.1 Hz), 151.47 (d, J = 4.6 Hz), 137.51 (d, J = 12.2 Hz), 135.23, 134.43, 130.44, 130.32, 129.92, 128.59, 126.17 (d, J = 8.2 Hz), 123.34 (d, J = 2.4 Hz), 123.16, 116.53 (d, J = 4.7 Hz), 113.39 (d, J = 19.2 Hz), 24.32, 12.91; HRMS (ESI) for C18H13ClFNO2 m/z: Calculated, 330.0692, found, 330.0697 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-chlorobenzoate (2m). White solid, yield 70.2%, mp 183~185 °C; 1H NMR (500 MHz, CDCl3) δ: 8.32–8.21 (m, 2H, Ph), 7.62–7.56 (m, 2H, Ph), 7.53–7.46 (m, 1H, Ph), 7.42–7.33 (m, 2H, Ph), 2.81 (s, 3H, CH3), 2.31 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 162.94, 160.85, 157.76 (d, J = 256.0 Hz), 151.50 (d, J = 4.6 Hz), 141.09, 137.55 (d, J = 12.2 Hz), 131.83 (2C), 129.40 (2C), 126.61, 126.10 (d, J = 8.2 Hz), 123.41 (d, J = 2.5 Hz), 123.17, 116.55 (d, J = 4.8 Hz), 113.33 (d, J = 19.2 Hz), 24.39, 12.90; HRMS (ESI) for C18H13ClFNO2 m/z: Calculated, 330.0692, found, 330.0697 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 4-isopropylbenzoate (2n). White solid, yield 46.5%, mp 144~146 °C; 1H NMR (500 MHz, CDCl3) δ: 8.29–8.21 (m, 2H, Ph), 7.57–7.50 (m, 1H, Ph), 7.45 (d, J = 8.2 Hz, 2H, Ph), 7.40–7.30 (m, 2H, Ph), 3.13–2.99 (m, 1H, CH), 2.80 (s, 3H, CH3), 2.32 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 163.76, 160.82, 157.73 (d, J = 255.7 Hz), 156.14, 151.82 (d, J = 4.5 Hz), 137.53 (d, J = 12.2 Hz), 130.73 (2C), 127.11 (2C), 125.91 (d, J = 8.2 Hz), 125.76, 123.68 (d, J = 2.3 Hz), 123.28 (s), 116.80 (d, J = 4.7 Hz), 113.18 (d, J = 19.2 Hz), 34.47, 24.38, 23.69 (2C), 12.87; HRMS (ESI) for C21H20FNO2 m/z: Calculated, 338.1551, found, 338.1556 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl 2-nitrobenzoate (2o). White solid, yield 46.3%, mp 204~206 °C, 1H NMR (500 MHz, CDCl3) δ: 9.17 (t, J = 1.8 Hz, 1H, Ph), 8.64 (d, J = 7.7 Hz, 1H, Ph), 8.62–8.57 (m, 1H, Ph), 7.84 (t, J = 8.0 Hz, 1H, Ph), 7.51–7.46 (m, 1H, Ph), 7.43–7.35 (m, 2H, Ph), 2.83 (s, 3H, CH3), 2.34 (s, 3H, CH3); 13C NMR (151 MHz, CDCl3) δ: 161.77, 160.90, 157.78 (d, J = 256.3 Hz), 151.16 (d, J = 4.6 Hz), 148.64, 137.60 (d, J = 12.2 Hz), 135.99, 130.38, 129.98, 128.74, 126.32 (d, J = 8.3 Hz), 125.34, 123.08 (d, J = 2.4 Hz), 123.06, 116.32 (d, J = 4.7 Hz), 113.50 (d, J = 19.2 Hz), 24.41, 12.97; HRMS (ESI) for C18H13FN2O4 m/z: Calculated, 341.0932, found, 341.0938 [M + H]+.
8-fluoro-2,3-dimethylquinolin-4-yl cyclopropanecarboxylate (2p). White solid, yield 32.8%, mp 115~117 °C; 1H NMR (500 MHz, CDCl3) δ: 7.51 (d, J = 8.3 Hz, 1H, Ph), 7.44–7.38 (m, 1H, Ph), 7.37–7.30 (m, 1H, Ph), 2.77 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.09–2.02 (m, 1H, CH), 1.32–1.28 (m, 2H, CH2), 1.21–1.12 (m, 2H, CH2); 13C NMR (151 MHz, CDCl3) δ: 171.99, 160.75, 157.71 (d, J = 255.6 Hz), 151.42 (d, J = 4.5 Hz), 137.47 (d, J = 12.1 Hz), 125.88 (d, J = 8.2 Hz), 123.57 (d, J = 2.5 Hz), 123.06, 116.61 (d, J = 4.6 Hz), 113.13 (d, J = 19.2 Hz), 24.35, 12.71, 12.66, 9.57 (2C); HRMS (ESI) for C15H14FNO2 m/z: Calculated, 260.1081, found, 260.1087 [M + H]+.

3.3. Fungicide Bioassays

The fungicidal activities of title chiral niacinamide derivatives 2a–2p were tested in vitro against A. solani (AS), G. zeae (GZ), P. oryae (PO), P. capsici (PC), S. sclerotiorum (SS), B. cinerea (BC), R. solani (RS), F. oxysporum (FO), C. arachidicola (CA), and P. piricola (PP), and their relative percent inhibition (%) was determined using the mycelium growth rate method according to the previous work [34,35]. Tebufloquin was used as the positive control. Each compound was dissolved in DMSO with 1% Tween to prepare the 500 μg/mL stock solution. The ten fungi were inoculated into a Petri dish containing 50 μg/mL stock solution and incubated in a 27 °C incubator. A DMSO solvent containing 1% Tween was used as a blank assay. The fungicidal effect was determined 48–72 h later. The inhibition rate of the compound compared to the blank assay was calculated by the following equation:
inhibition (%) = (CK − AI)/CK × 100%
where CK is the average diameter of the mycelium in the blank test, and AI is the average value of the mycelium in the presence of these compounds.

3.4. Crystal Structure

The structure of compound 8-fluoro-2,3-dimethylquinolin-4-yl 4-(tert-butyl)benzoate 2b was further characterized by single-crystal X-ray diffraction, and is illustrated in Figure 3. As shown in Figure 3, the phenyl ring (C(13)~C(18) is nearly vertical with the quinoline ring, which has a dihedral angle (θ) of 76.2° with plane equation 2.499x + 3.956y + 7.124z = 5.9084 and 5.915x + 3.757y + −6.977z = 3.1104, respectively. The torsion angles of C(9)-O(1)-C(12)-C(13) and O(2)-C(12)-C(13)-C(14) were −171.3(3)° and −175.7(3)°, respectively, which showed that the ester group is nearly in the same plane as the phenyl ring. Compound 2b had weak interaction, which formed an infinite one-dimensional chain structure along the a-axis (Figure 4).

4. Conclusions

In summary, sixteen new fluorinated quinoline compounds were synthesized, and their structures were characterized by 1H NMR, 13C NMR, X-ray diffraction, and HRMS. The antifungal activity results showed that some of the compounds exhibited good antifungal activity at 50 μg/mL. Among them, compounds 2b, 2e, 2f, 2k, and 2n exhibited good antifungal activity (>80%) against S. sclerotiorum. The antifungal activity of compound 2g against R. solani was 80.8%. This can give new clues for designing new highly active quinoline compounds in the next study.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28083373/s1, Figures for 1H NMR, 13C NMR, and HRMS.

Author Contributions

Methodology and Investigation, X.S. and W.Y.; editing, L.M. and J.S.; Resources, L.H.; Writing—review & editing, X.H.; Supervision, N.S. and X.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by Zhejiang Provincial Natural Science Foundation of China (No. LTGN23C140002, LY19C140002, LY19B020009), Natural Science Foundation of China (No. 32001929), the Talent Start Foundation of Huangshan University (No. 2018xkjq018), and the Chemical Company for Research (KYY-HX-20210140, KYY-HX-20190720).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article or Supplementary Material.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 28 03373 g001 550
Figure 1. Some commercialized pesticides or drugs with fluorinated quinoline derivatives.
Figure 1. Some commercialized pesticides or drugs with fluorinated quinoline derivatives.
Molecules 28 03373 g001
Molecules 28 03373 g002 550
Figure 2. Design strategy of the title compounds 2a–2p [32].
Figure 2. Design strategy of the title compounds 2a–2p [32].
Molecules 28 03373 g002
Molecules 28 03373 sch001 550
Scheme 1. Synthesis route of title compounds 2a–2p.
Scheme 1. Synthesis route of title compounds 2a–2p.
Molecules 28 03373 sch001
Molecules 28 03373 g003 550
Figure 3. Molecular structure of the title compound 2b.
Figure 3. Molecular structure of the title compound 2b.
Molecules 28 03373 g003
Molecules 28 03373 g004 550
Figure 4. Chain structure of compound 2b.
Figure 4. Chain structure of compound 2b.
Molecules 28 03373 g004
Table
Table 1. Solvent effect of yield compound 2b.
Table 1. Solvent effect of yield compound 2b.
SolventYield (%)
DMF32.5
CH2Cl259.3
Table
Table 2. Crystal data and structure refinement of compound 2b.
Table 2. Crystal data and structure refinement of compound 2b.
Name2b
Empirical formulaC22H22FNO2
Formula weight351.40
Temperature/K296(2)
Crystal systemtriclinic
Space groupP-1
a/Å8.4459(10)
b/Å10.2380(12)
c/Å11.7771(14)
α/°101.100(6)
β/°98.283(6)
γ/°108.547(6)
Volume/Å3924.05(19)
Z2
ρcalcg/cm31.263
μ/mm−10.087
F(000)372.0
Crystal size/mm30.36 × 0.28 × 0.18
RadiationMoKα (λ = 0.71073)
2Θ range for data collection/°4.89 to 57.452
Index ranges−11 ≤ h ≤ 10, −13 ≤ k ≤ 13, −15 ≤ l ≤ 15
Reflections collected13,642
Independent reflections4164 [Rint = 0.0755, Rsigma = 0.1961]
Data/restraints/parameters4164/0/240
Goodness-of-fit on F21.172
Final R indexes [I ≥ 2σ (I)]R1 = 0.1333, wR2 = 0.2614
Final R indexes [all data]R1 = 0.3507, wR2 = 0.3608
Largest diff. peak/hole/e Å−31.19/−1.24
Table
Table 3. The fungicidal activity (% inhibition) of compounds 2a–2p and Tebufloquin (FP) at 50 μg/mL on A. solani (AS), G. zeae (GZ), P. oryae (PO), P. capsici (PC), S. sclerotiorum (SS), B. cinerea (BC), R. solani (RS), F. oxysporum (FO), C. arachidicola (CA), and P. piricola (PP). CK = control.
Table 3. The fungicidal activity (% inhibition) of compounds 2a–2p and Tebufloquin (FP) at 50 μg/mL on A. solani (AS), G. zeae (GZ), P. oryae (PO), P. capsici (PC), S. sclerotiorum (SS), B. cinerea (BC), R. solani (RS), F. oxysporum (FO), C. arachidicola (CA), and P. piricola (PP). CK = control.
No.ASGZPOPCSSBCRSFOCAPP
2a37.5 12.5 10.0 29.0 38.5 7.7 30.8 20.0 13.3 20.0
2b43.8 33.3 50.0 32.3 84.6 53.8 50.0 20.0 46.7 48.0
2c25.0 25.0 20.0 12.9 38.5 46.2 11.5 15.0 20.0 36.0
2d25.0 29.2 40.0 32.3 69.2 53.8 38.5 10.0 33.3 44.0
2e56.3 29.2 20.0 38.7 80.8 26.9 11.5 45.0 33.3 72.0
2f37.5 25.0 40.0 58.1 88.5 50.0 38.5 20.0 46.7 76.0
2g43.8 8.3 10.0 25.8 38.5 15.4 80.8 35.0 26.7 36.0
2h18.8 16.7 20.0 22.6 46.2 23.1 38.5 15.0 13.3 40.0
2i25.0 4.2 20.0 25.8 53.8 30.8 50.0 20.0 26.7 24.0
2j25.0 16.7 8.0 32.3 46.2 11.5 46.2 45.0 26.7 36.0
2k25.0 12.5 20.0 48.4 84.6 38.5 38.5 20.0 33.3 76.0
2l12.5 4.2 8.0 32.3 50.0 26.9 11.5 20.0 20.0 28.0
2m18.8 4.2 8.0 16.1 57.7 19.2 19.2 15.0 13.3 36.0
2n37.5 33.3 20.0 29.0 84.6 57.7 69.2 35.0 60.0 76.0
2o37.5 12.5 8.0 25.8 53.8 23.1 38.5 15.0 20.0 8.0
2p43.8 25.0 40.0 45.2 57.7 42.3 76.9 25.0 26.7 28.0
FP83.3 85.4 63.6 58.1 75.0 56.7 69.7 42.9 37.5 65.4
CK0.00.00.00.00.00.00.00.00.00.0
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Sun, X.; Yu, W.; Min, L.; Han, L.; Hua, X.; Shi, J.; Sun, N.; Liu, X. Synthesis, Structural Determination, and Antifungal Activity of Novel Fluorinated Quinoline Analogs. Molecules 2023, 28, 3373. https://doi.org/10.3390/molecules28083373

AMA Style

Sun X, Yu W, Min L, Han L, Hua X, Shi J, Sun N, Liu X. Synthesis, Structural Determination, and Antifungal Activity of Novel Fluorinated Quinoline Analogs. Molecules. 2023; 28(8):3373. https://doi.org/10.3390/molecules28083373

Chicago/Turabian Style

Sun, Xinpeng, Wei Yu, Lijing Min, Liang Han, Xuewen Hua, Jianjun Shi, Nabo Sun, and Xinghai Liu. 2023. "Synthesis, Structural Determination, and Antifungal Activity of Novel Fluorinated Quinoline Analogs" Molecules 28, no. 8: 3373. https://doi.org/10.3390/molecules28083373

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