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Article

Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo

by
Bin-Long Sun
,
Ying-Ying Wang
,
Sen Yang
,
Min-Ting Tu
,
Ying-Ying Shao
,
Yi Hua
,
Yi Zhou
and
Cheng-Xia Tan
*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(12), 3946; https://doi.org/10.3390/molecules27123946
Submission received: 23 May 2022 / Revised: 16 June 2022 / Accepted: 16 June 2022 / Published: 20 June 2022
(This article belongs to the Special Issue Bioactive Molecules: Isolation, Synthesis, Analysis, and Application in Medicinal Chemistry)
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Abstract

:
To develop new compounds with high activity, broad spectrum and low-toxicity, 17 benzamides substituted with quinoline-linked 1,2,4-oxadiazole were designed using the splicing principle of active substructures and were synthesized. The biological activities were evaluated against 10 fungi, indicating that some of the synthetic compounds showed excellent fungicidal activities. For example, at 50 mg/L, the inhibitory activity of 13p (3-Cl-4-Cl substituted, 86.1%) against Sclerotinia sclerotiorum was superior to that of quinoxyfen (77.8%), and the inhibitory activity of 13f (3-CF3 substituted, 77.8%) was comparable to that of quinoxyfen. The fungicidal activities of 13f and 13p to Sclerotinia sclerotiorum were better than that of quinoxyfen (14.19 mg/L), with EC50 of 6.67 mg/L and 5.17 mg/L, respectively. Furthermore, the acute toxicity of 13p was 19.42 mg/L, classifying it as a low-toxic compound.

1. Introduction

Possessing different biological activity, heterocyclic structures like nitrogen-containing heterocyclic [1,2] and oxygen-containing heterocyclic are important features in synthetic pesticides for their high efficiency, various biological activities, and diversity of possible substituents. Quinoline is a versatile group, a privileged scaffold, and an outstanding fused heterocyclic compound [3]. Apart from their applications in medicine [4], quinoline derivatives have shown potential in pesticides, such as insecticidal [5,6,7], herbicidal [8] and fungicidal activities [9,10,11,12]. As the bioisostere of the amide, the 1,2,4-oxadiazole heterocycle has good hydrolytic and metabolic properties [13], and exhibits a wide range of biological activities in the field of pesticides [14,15,16,17,18,19]. In addition, there have already been quite a few products containing quinoline or 1,2,4-oxadiazole scaffold launched successively, including quinoxyfen [20], ipflufenoquin [21], quinmerac, tioxazafen and oxolamine (Figure 1).
In our efforts to develop potent fungicides, we have previously reported the synthesis and biological activity studies of 1,2,4-oxadiazole-substituted benzamide derivatives [22,23]. Some of them exhibited good fungicidal activities. In view of the facts mentioned above, to further improve the fungicidal activities of these compounds, we designed (Figure 2) a series of novel 1,2,4-oxadiazole-substituted benzamides using the splicing principle of active substructures and synthesized them by introducing a quinoline scaffold at the 5-position of 1,2,4-oxadiazole. The chemical structures of these new compounds were confirmed by 1H-NMR, 13C-NMR, and HRMS, their fungicidal activities were studied and a toxicity test with zebrafish embryo was performed.

2. Results and Discussion

2.1. Synthesis of Target Compounds

The synthetic pathway to target compounds 13a–13q is shown in Scheme 1. The starting material 3,5-dichloroaniline 1 underwent addition, hydrolysis, cyclization, and oxidation reaction to give 5,7-dichloro-4-hydroxyquinoline 5. During the addition reaction (the first reaction in Scheme 1), methanesulfonic acid (MSA) was selected as the acid catalyst and the optimum molar ratio of 1:0.2 was determined, which greatly improved the yield of the reaction. In step 4, we performed a preliminary screening of the oxidant, and finally determined to take the K2S2O8/H2SO4 system as the oxidant to afford compound 5 in the best yield. The influence of different reaction conditions on the yield of the compound 5 is shown in Table 1. Moreover, acetonitrile was chosen as the solvent in which the product had low solubility so that it could precipitate to obtain the solid easily.
The synthesis of amine oxime 9 was similar to our previous procedures [23]. It should be noted that this reaction could not be carried out for a long time to avoid the form of amide by-products. Afterwards, intermediate 12 was prepared from compound 9 via cyclization, hydrolysis, and condensation reaction. In addition, the hydrolysis reaction was carried out under acidic condition to avoid by-products as chlorine-substituted alkanes would hydrolyzed readily than ester groups under alkaline condition (Scheme 2).
Finally, Williamson ether synthesis of compound 5 with 12 formed the target compounds 13.

2.2. Spectrum Analysis of Target Compounds

All the target compounds were confirmed by 1H-NMR, 13C-NMR, and HRMS. The target compound 13f was taken as an example to conduct spectrum analysis. In the 1H-NMR spectra of 13f, the –NH– proton signal was found at δ 10.75 ppm. In addition, the single peak at 6.04 ppm was the peak of –CH2– between ether bond and 1,2,4-oxadiazoles. In the 13C-NMR spectra of compound 13f, the appearances of signals at 167.83 ppm and 165.40 ppm were assigned to the carbons of the 1,2,4-oxadiazole ring. In the HRMS spectrogram, the calculated value of the ion peak of this compound was [M + Na]+ 559.0546, and the measured value was [M + Na]+ 559.0549. The absolute error was within 0.003.

2.3. Biological Activities of Target Compounds

The results of the fungicidal activities test of the target compounds against 10 fungi are shown in Table 2. At 50 mg/L, all the target compounds 13a–13q were found to exhibit certain inhibitory activity against the 10 fungi tested. Overall, the target compounds showed better inhibitory activity against Sclerotinia sclerotiorum, ranging from 47.2% to 86.1%. Among them, the inhibitory rate of compound 13p (86.1%) was superior to the control drug quinoxyfen (77.8%), and the inhibitory rate of compound 13f was 77.8%, which was similar to quinoxyfen. In addition, the inhibition rates of compounds 13a, 13b, 13d and 13o against Sclerotinia sclerotiorum were 75.0%, 72.2%, 75.0% and 75.0%, respectively, which are slightly lower than that of quinoxyfen. Other compounds also exhibited moderate inhibitory activity (47.2–69.4%). For Alternaria solani, Gibberella zeae, Phytophthora capsica and Physalospora piricola, some compounds possessed better inhibitory activities than quinoxyfen, but their inhibition rates were less than 50%. As can be seen from Table 3, the EC50 of compounds 13f and 13p against Sclerotinia sclerotiorum were 6.67 mg/L and 5.17 mg/L, respectively, which were significantly superior to quinoxyfen (14.19 mg/L). Structure–activity relationship (SAR) results for these target compounds showed that when the substituent of the benzene ring was 3-CF3 or 3,4-(Cl)2, their inhibitory activities were obviously superior to others. Overall, electron withdrawing groups are beneficial to inhibitory activity.

2.4. Toxicity to Zebrafish Embryo

According to the fungicidal activity results (Figure 3), we selected compound 13p with better activity to study the lethal and teratogenic effects exposure on zebrafish embryos from 6 to 96 hpf (hours post fertilization). When the concentration of 13p was below 40 mg/L, the mortality rate increased sharply as the concentration increased. Afterwards, the mortality rate exceeded 90% at 40 mg/L. The resulting LC50 value for compound 13p was 19.42 mg/L, and it was classified as a low-toxic compound [24].
As the time and concentration increased, zebrafish embryos showed obvious developmental delay (Figure 4), such as bent spine, pericardial cyst, yolk cyst and even malformation. At 72 hpf, compared to the control group, the zebrafish embryo exposed at 10 mg/L and 20 mg/L showed obvious yolk cyst. At 96 hpf, pericardial cyst and bent spine appeared on the zebrafish embryo exposed at 10 mg/L and 20 mg/L.

3. Experimental Section

3.1. General Information

Melting points were determined using an X-4 digital microscopic melting point detector (Taike, Beijing, China) and the thermometer was uncorrected. 1H-NMR and 13C-NMR spectra were measured on BRUKER Avance 500 MHz spectrometer (Bruker 500 MHz, Fallanden, Switzerland) using CDCl3 or DMSO as the solvent. High-resolution electrospray mass spectra (HR-ESI–MS) were determined using an UPLC H CLASS/QTOF G2 XS mass spectrometer (Waters, Milford, CT, USA). All the reagents were analytical grade or synthesized in our laboratory. The characterization data for all synthetic compounds are provided in the Supplementary Materials.
Ethics statement: The Institutional Animal Care and Use Committee (IACUC) at Wenzhou Medical University (SYXK 2019-0009, 4 April 2019 to 4 April 2024) approved our study plan for proper use of zebrafish. All studies were carried out in strict accordance with the guidelines of the IACUC. All dissections were performed on ice, and all efforts were made to minimize suffering.

3.2. Synthesis

3.2.1. Ethyl 3-((3,5-dichlorophenyl)amino)propanoate (2)

3,5-dichloroaniline 1 (16.20 g, 0.10 mol) and ethyl acrylate (30.00 g, 0.30 mol) were sequentially added to a three-necked flask, heated, and stirred until dissolved completely. The mixture of MSA (1.44 g) and water (2.70 g) was added dropwise, then reacted at 60 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, unreacted ethyl acrylate was removed under reduced pressure. The remnant was dissolved in toluene (300 mL) and washed with HCl. Finally, the organic layer was dried with anhydrous MgSO4 and evaporated to give 23.60 g yellow solid. Yield: 90.0%, m.p. 72–74 °C; 1H-NMR (500 MHz, Chloroform-d) δ 6.69 (t, J = 1.7 Hz, 1H), 6.48 (d, J = 1.8 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

3.2.2. 3-((3,5-Dichlorophenyl)amino)propanoic Acid (3)

Ethyl 3-((3,5-dichlorophenyl)amino)propanoate 2 (31.32 g, 0.12 mol), methanol (50 mL) and NaOH (20%, 32.00 g) were added to a three-necked flask and reacted at 60 °C for 1 h. Methanol was removed under reduced pressure followed by the addition of water (100 mL). Afterwards, we adjusted the pH to 2–3 with HCl and white solid precipitate was obtained (24.50 g). Yield: 85%, m.p. 102–103 °C.

3.2.3. 5,7-Dichloro-2,3-dihydroquinolin-4(1H)-one (4)

To a three-necked flask, we added PPA (10.00 g) and heat at 90 °C for 0.5 h. Then, 3-((3,5-dichlorophenyl)amino)propanoic acid 3 (4.66 g, 0.02 mol) was added slowly and reacted at 150 °C for 5 h. To the stirred solution, water (100 mL) was added to precipitate yellow solid after the mixture was cooled to room temperature. The crude product was filtered, sequentially washed with petroleum ether and saturated aqueous NaHCO3 solution, and dried to obtain 4.30 g solid. Yield: 94%, m.p. 184–185 °C.

3.2.4. 5,7-Dichloro-4-hydroxyquinoline (5)

Conc. H2SO4 (2.00 g) was added slowly to a solution of compound 4 (5.00 g, 23.00 mmol) in acetonitrile (35.00 g). Afterwards, K2S2O8 (8.00 g) was added when the temperature reached 50 °C. The mixture was then reflux for 4 h. TLC was used to track the reaction progress. After the reaction was completed, the mixture was cooled to room temperature to precipitate solid. The solid was filtered, washed with water, and dried to obtain product 5 (4.60 g). Yield: 93.4%.

3.2.5. Methyl-3-(N-hydroxycarbamimidoyl)benzoate (9)

The synthesis of intermediate 9 was performed with reference to our previous work.

3.2.6. Methyl 3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)benzoate (10)

To a three-necked flask, we added intermediate 9 (0.97 g, 5.00 mmol), triethylamine (1.20 g, 12.00 mmol) and dry toluene (100 mL). Stirring was started at 0 °C for 2 h followed by the dropwise addition of chloroacetyl chloride (0.58 g, 5.20 mmol). This was then reacted at 0 °C for another 3 h. The mixture was further heated to reflux for about 2 h. The mixture was then cooled to room temperature and sequentially washed with water and saturated sodium chloride solution. The organic layer was dried with Na2SO4 and the solvent was removed to give 0.93 g yellow solid. Yield: 73.8%; 1H-NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 4.78 (s, 2H), 3.97 (s, 3H).

3.2.7. 3-(5-(Chloromethyl)-1,2,4-oxadiazol-3-yl)benzoic Acid (11)

Compound 10 (5.00 g, 0.02 mol), CH3COOH (30 mL), and HCl (30 mL) were added to a three-necked flask and reacted at 70 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature to precipitate white solid. The white solid was filtered, washed with water, and dried to give compound 11 (4.45 g). Yield: 93.6%, m.p. 179–182 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.53 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 5.19 (s, 2H).

3.2.8. Synthesis of Intermediate (12)

The solution of compound 11 (0.24 g, 1.00 mmol) in SOCl2 (5 mL) was reacted at reflux for 3 h. The SOCl2 was removed and THF (30 mL) was added subsequently. Then, the mixture of substituted aniline (1.20 mmol), triethylamine (2.5 mmol) and THF (1 mL) was added dropwise under ice bath. Stirred overnight, separated by column chromatography to give intermediate 12.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-phenylbenzamide12a. Yellow solid, yield 79.4%, m.p. 103–104 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.60 (s, 1H), 8.22 (t, J = 9.0 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.33, 168.18, 165.05, 139.41, 136.45, 131.42, 130.36, 130.06, 129.09, 126.82, 126.36, 124.37, 121.03, 34.21; HRMS calcd for C16H12ClN3O2 [M + H]+ 314.0691, found 314.0698.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(o-tolyl)benzamide12b. Yellow solid, yield 77.5%, m.p. 95–96 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.64 (t, J = 1.8 Hz, 1H), 8.24 (d, J = 7.7 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.27–7.17 (m, 2H), 5.23 (s, 2H), 2.26 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 176.32, 168.20, 164.91, 136.69, 136.07, 134.33, 131.31, 130.81, 130.32, 130.09, 127.17, 126.89, 126.64, 126.50, 126.41, 34.22, 18.39; HRMS calcd for C17H15ClN3O2 [M + H]+ 328.0847, found 328.0856.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(m-tolyl)benzamide12c. White solid, yield 69.7%, m.p. 98–100 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H), 2.33 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 176.32, 168.18, 164.96, 139.33, 138.25, 136.49, 131.40, 130.32, 130.05, 128.92, 126.78, 126.35, 125.06, 121.55, 118.20, 34.21, 21.66; HRMS calcd for C17H15ClN3O2 [M + H]+ 328.0847, found 328.0857.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(p-tolyl)benzamide12d. White solid, yield 73.8%, m.p. 113–116 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.59 (s, 1H), 8.24–8.18 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 5.23 (s, 2H), 2.29 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 176.31, 168.19, 164.82, 136.89, 136.51, 133.35, 131.36, 130.26, 130.02, 129.47, 126.78, 126.34, 121.04, 34.21, 20.97; HRMS calcd for C17H15ClN3O2 [M + H]+ 328.0847, found 328.0854.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(4-(tert-butyl)phenyl)benzamide12e. White solid, yield 75.7%, m.p. 125–127 °C; 1H-NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.64–7.54 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 4.76 (s, 2H), 1.34 (s, 9H); 13C-NMR (126 MHz, DMSO-d6) δ 167.72, 167.21, 164.88, 150.40, 146.74, 136.83, 136.53, 131.31, 130.51, 130.01, 126.94, 126.34, 125.71, 124.92, 120.74, 111.70, 41.05, 34.55, 31.67, 19.01, 12.96; HRMS calcd for C20H21ClN3O2 [M + H]+ 370.1317, found 370.1327.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(3-(trifluoromethyl)phenyl)benzamide12f. Yellow solid, yield 66.4%, m.p. 141–145 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.31–8.17 (m, 3H), 8.10 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.60, 167.19, 165.40, 150.37, 140.21, 135.87, 131.37, 130.86, 130.33, 130.02 (d, J = 11.5 Hz), 126.97, 126.43, 125.69, 124.85, 124.38, 123.52, 120.63 (d, J = 3.8 Hz), 116.99 (d, J = 4.0 Hz), 111.72, 41.03, 18.98, 12.90; HRMS calcd for C17H12ClF3N3O2 [M + H]+ 382.0565, found 382.0576.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(2-fluorophenyl)benzamide12g. Yellow solid, yield 75.9%, m.p. 107–109 °C; 1H-NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.41 (t, J = 8.0 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.22–7.17 (m, 1H), 7.16–7.09 (m, 2H), 4.78 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.65, 167.19, 165.05, 157.29, 155.32, 150.38, 135.43, 131.45, 130.82, 130.10, 127.63 (d, J = 10.1 Hz), 127.06, 126.40, 125.98 (d, J = 12.2 Hz), 124.87, 124.79 (d, J = 3.5 Hz), 116.33 (d, J = 19.9 Hz), 111.71, 41.03, 19.00, 12.92; HRMS calcd for C16H12ClFN3O2 [M + H]+ 332.0597, found 332.0606.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(3-fluorophenyl)benzamide12h. Yellow solid, yield 78.6%, m.p. 123–127 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.59 (t, J = 1.5 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.82–7.74 (m, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.45–7.37 (m, 1H), 6.97 (t, J = 8.5 Hz, 1H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.10, 166.68, 164.79, 162.97, 161.05, 149.86, 140.67 (d, J = 11.3 Hz), 135.55, 130.85, 130.20 (d, J = 10.1 Hz), 129.53, 126.45, 125.89, 124.34, 116.06, 111.22, 110.29 (d, J = 21.1 Hz), 107.08 (d, J = 26.3 Hz), 40.54, 18.49, 12.40; HRMS calcd for C16H12ClFN3O2 [M + H]+ 332.0597, found 332.0604.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(4-fluorophenyl)benzamide12i. Yellow solid, yield 67.1%, m.p. 132–133 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.60 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.86–7.80 (m, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.68, 167.21, 165.00, 159.86, 157.95, 150.39, 136.29, 135.74, 131.32, 130.63, 130.06, 126.91, 126.38, 124.90, 122.84 (d, J = 7.8 Hz), 115.69 (d, J = 22.2 Hz), 111.70, 41.05, 19.00, 12.95; HRMS calcd for C16H12ClFN3O2 [M + H]+ 332.0597, found 332.0601.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(4-chlorophenyl)benzamide12j. Yellow solid, yield 79.3%, m.p. 149–151 °C; 1H-NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.67–7.57 (m, 3H), 7.34 (d, J = 8.8 Hz, 2H), 4.78 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.67, 167.23, 165.08, 150.41, 135.52, 135.35, 131.37, 130.86, 130.20, 130.17, 130.08, 129.09, 128.20, 128.00, 127.05, 126.47, 124.93, 111.70, 41.05, 19.01, 12.96; HRMS calcd for C16H12Cl2N3O2 [M + H]+ 348.0301, found 348.0312.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(4-bromophenyl)benzamide12k. Yellow solid, yield 73.4%, m.p. 153–155 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.82–7.73 (m, 3H), 7.56 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.61, 167.18, 165.27, 150.37, 140.89, 135.99, 133.43, 131.36, 130.77, 130.05, 126.96, 126.40, 124.85, 124.03, 120.34, 119.22, 111.72, 41.04, 18.99, 12.91; HRMS calcd for C16H12ClBrN3O2 [M + H]+ 391.9796, found 391.9802.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(4-iodophenyl)benzamide12l. Yellow solid, yield 68.8%, m.p. 141–143 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.69, 167.25, 165.21, 150.41, 138.39, 136.23, 131.42, 130.75, 130.12, 129.04, 128.02, 126.96, 126.41, 124.94, 122.49, 111.70, 41.06, 19.01, 12.98; HRMS calcd for C16H12ClIN3O2 [M + H]+ 439.9657, found 439.9668.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(2,4-dimethylphenyl)benzamide12m. White solid, yield 69.5%, m.p. 114–117 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.63 (s, 1H), 8.22 (d, J = 7.8 Hz, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.22 (s, 2H), 2.30 (s, 3H), 2.21 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 167.68, 167.24, 165.21, 150.41, 138.81, 136.22, 131.96, 131.41, 130.76, 130.12, 126.96, 126.41, 124.93, 122.85, 116.11, 111.70, 41.06, 19.01, 12.97; HRMS calcd for C18H17ClN3O2 [M + H]+ 342.1004, found 342.1013.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(2,6-dimethylphenyl)benzamide12n. White solid, yield 74.4%, m.p. 125–129 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.65 (t, J = 1.7 Hz, 1H), 8.28–8.22 (m, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.15 (s, 3H), 5.23 (s, 2H), 2.22 (s, 6H); 13C-NMR (126 MHz, DMSO-d6) δ 167.68, 167.24, 165.20, 150.41, 139.29, 137.80, 136.25, 131.41, 130.75, 130.10, 126.96, 126.40, 124.93, 123.09, 111.70, 88.14, 41.06, 19.01, 12.98; HRMS calcd for C18H17ClN3O2 [M + H]+ 342.1004, found 342.1016.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(3-chloro-2-methylphenyl)benzamide12o. White solid, yield 63.7%, m.p. 107–109 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.63 (s, 1H), 8.24 (t, J = 8.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 5.23 (s, 2H), 2.27 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 167.72, 167.17, 164.89, 150.38, 136.10, 135.75, 134.05, 131.34, 131.24, 130.47, 130.02, 127.05, 127.02, 126.98, 126.36, 124.89, 111.69, 41.03, 21.02, 19.00, 18.29, 12.93; HRMS calcd for C17H14Cl2N3O2 [M + H]+ 362.0458, found 362.0459.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(3,4-dichlorophenyl)benzamide12p. Yellow solid, yield 64.9%, m.p. 138–140 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.59 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 7.81–7.74 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.70, 167.18, 164.58, 150.38, 136.06, 135.85, 135.54, 131.11, 130.53, 130.11, 128.24, 127.28, 126.88, 126.46, 124.88, 111.69, 41.03, 19.00, 18.53, 12.92; HRMS calcd for C16H11Cl3N3O2 [M + H]+ 381.9911, found 381.9921.
3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-(2,4-difluorophenyl)benzamide12q. Yellow solid, yield 63.7%, m.p. 121–124 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.63 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.68–7.57 (m, 1H), 7.39 (t, J = 9.8 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 5.23 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 167.67, 167.21, 165.13, 150.39, 138.31, 135.64, 134.30, 132.73, 131.37, 130.77, 130.14, 127.42, 127.39, 127.02, 126.43, 126.40, 124.90, 41.05, 19.00, 15.83, 12.95; HRMS calcd for C16H11ClF2N3O2 [M + H]+ 350.0502, found 350.0511.

3.2.9. Synthesis of Target Compound 13

5,7-dichloro-4-hydroxyquinoline 5 (0.21 g, 1.00 mmol), intermediate 12 (1.00 mmol), K2CO3 (0.35 g) and DMF (10 mL) were added to a round bottom flask. The mixture was reacted at 60 °C for 5 h. Afterwards, the mixture was cooled to room temperature and poured into water (100 mL) then extracted with ethyl acetate. The extraction was dried over anhydrous MgSO4 and filtered. After that the filtration was concentrated and separated by column chromatography to give target compounds 13.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-phenylbenzamide13a. Yellow solid, yield 67.6%, HPLC 90.45%, m.p. 221–224 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.48 (s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.13–8.05 (m, 2H), 7.89 (s, 1H), 7.77 (d, J = 7.7 Hz, 2H), 7.73–7.69 (m, 1H), 7.51 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.20 (d, J = 7.8 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.00, 175.93, 167.88, 165.02, 144.59, 143.61, 139.33, 136.83, 136.39, 135.00, 131.26, 130.42, 130.03, 129.89, 129.08, 126.78, 126.74, 126.28, 124.38, 121.01, 116.14, 113.04, 48.64; HRMS calcd for C25H17Cl2N4O3 [M + H]+ 491.0672, found 491.0671.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(o-tolyl)benzamide13b. Yellow solid, yield 64.2%, HPLC 93.24%, m.p. 237–238 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.25–7.15 (m, 2H), 6.20 (d, J = 7.9 Hz, 1H), 6.03 (s, 2H), 2.22 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 175.98, 175.95, 167.88, 164.93, 144.59, 143.60, 136.83, 136.58, 136.01, 134.99, 134.22, 131.17, 130.80, 130.38, 130.09, 127.10, 126.84, 126.74, 126.65, 126.50, 126.30, 121.82, 116.15, 113.03, 48.64, 18.30; HRMS calcd for C26H19Cl2N4O3 [M + H]+ 505.0829, found 505.0831.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(m-tolyl)benzamide13c. Yellow solid, yield 65.6%, HPLC 93.26%, m.p. 255–258 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.12–8.06 (m, 2H), 7.89 (d, J = 1.8 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H), 2.32 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 175.99, 175.92, 167.88, 164.93, 144.58, 143.61, 139.25, 138.25, 136.83, 136.43, 134.99, 131.23, 130.39, 130.01, 128.91, 126.76, 126.73, 126.27, 125.07, 121.83, 121.54, 118.18, 116.14, 113.04, 48.64, 21.64; HRMS calcd for C26H19Cl2N4O3 [M + H]+ 505.0829, found 505.0835.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(p-tolyl)benzamide13d. Yellow solid, yield 63.7%, HPLC 94.00%, m.p. 207–211 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.12–8.05 (m, 2H), 7.88 (d, J = 1.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H), 2.28 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 175.97, 175.93, 167.89, 164.79, 144.57, 143.59, 136.83, 136.80, 136.45, 135.00, 133.37, 131.19, 130.32, 129.98, 129.87, 129.45, 126.75, 126.26, 121.83, 121.02, 116.12, 113.04, 48.63, 20.95; HRMS calcd for C26H19Cl2N4O3 [M + H]+ 505.0829, found 505.0832.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(4-(tert-butyl)pheny-l)-benzamide13e. Yellow solid, yield 65.1%, HPLC 96.69%, m.p. 253–255 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.09 (t, J = 7.2 Hz, 2H), 7.88 (s, 1H), 7.74–7.63 (m, 3H), 7.51 (s, 1H), 7.37 (d, J = 7.5 Hz, 2H), 6.20 (d, J = 7.3 Hz, 1H), 6.04 (s, 2H), 1.28 (s, 9H); 13C-NMR (126 MHz, DMSO-d6) δ 175.99, 175.96, 167.89, 164.84, 146.80, 144.61, 143.60, 136.85, 136.72, 136.42, 135.00, 131.21, 130.37, 130.03, 129.14, 126.75, 126.26, 125.70, 121.82, 120.79, 116.15, 113.04, 48.64, 34.53, 31.65; HRMS calcd for C29H25Cl2N4O3 [M + H]+ 547.1298, found 547.1301.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-(trifluoromthyl)p-henyl)benzamide13f.Yellow solid, yield 57.3%, HPLC 95.23%, m.p. 214–216 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 8.10–8.03 (m, 2H), 7.88 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.51–7.44 (m, 2H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.01, 175.96, 167.83, 165.40, 144.58, 143.58, 140.13, 136.84, 135.84, 135.00, 131.34, 130.75, 130.32, 130.12, 129.85 (q, J = 130 Hz), 126.75 (d, J = 4.5 Hz), 126.36, 125.65, 124.43, 123.49, 121.82, 120.66, 117.04 (d, J = 15 Hz), 116.11, 113.04, 48.64; HRMS calcd for C26H16Cl2F3N4O3 [M + H]+ 559.0546, found 559.0549.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-fluorophenyl)benzamide13g. Yellow solid, yield 59.6%, HPLC 96.30%, m.p. 240–242 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.51 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 7.7 Hz, 1H), 8.09–8.07 (m, 1H), 7.89 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.34–7.27 (m, 2H), 7.26–7.20 (m, 1H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.00, 175.93, 167.85, 165.04, 157.24, 155.28, 144.58, 143.60, 136.83, 135.40, 135.00, 131.35, 130.68, 130.12, 129.88, 127.63, 126.90, 126.73, 126.33, 124.77, 121.83, 116.38, 116.17 (d, J = 11.7 Hz), 113.04, 48.64; HRMS calcd for C25H16Cl2FN4O3 [M + H]+ 509.0578, found 509.0581.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-fluorophenyl)benzamide13h. Yellow solid, yield 59.3%, HPLC 91.69%, m.p. 233–236 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.77–7.68 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.43–7.36 (m, 1H), 6.95 (t, J = 7.0 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 175.99, 175.96, 167.83, 165.29, 163.45, 161.53, 144.58, 143.58, 141.09 (d, J = 10.9 Hz), 136.84, 136.03, 135.01, 134.18, 131.30, 130.69 (d, J = 11.3 Hz), 130.09, 129.86, 126.76 (d, J = 7.1 Hz), 121.82, 116.61, 116.11, 113.04, 110.82 (d, J = 21.0 Hz), 107.64 (d, J = 26.0 Hz), 48.63; HRMS calcd for C25H16Cl2FN4O3 [M + H]+ 509.0578, found 509.0583.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(4-fluorophenyl)benzamide13i. Yellow solid, yield 61.6%, HPLC 92.59%, m.p. 246–248 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.12–8.06 (m, 2H), 7.89–7.86 (s, 1H), 7.80–7.75 (m, 2H), 7.71 (t, J = 7.7 Hz, 1H), 7.50 (s, 1H), 7.20 (t, J = 8.6 Hz, 2H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 175.98, 175.96, 167.86, 165.49, 164.94, 159.86, 157.95, 144.58, 143.59, 136.84, 136.19, 135.65 (d, J = 2.3 Hz), 135.01, 134.19, 131.21, 130.47, 129.95 (d, J = 22.4 Hz), 126.74, 126.30, 122.88 (d, J = 7.9 Hz), 121.82, 116.11, 115.65 (d, J = 22.2 Hz), 113.04, 48.63; HRMS calcd for C25H16Cl2FN4O3 [M + H]+ 509.0578, found 509.0576.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(4-chlorophenyl)benzamide13j. Yellow solid, yield 61.7%, HPLC 92.14%, m.p. 254–257 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.09–8.06 (m, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 175.99, 175.95, 167.84, 165.11, 144.58, 143.59, 138.29, 136.84, 136.10, 135.00, 131.28, 130.57, 130.07, 128.99, 128.04, 126.78, 126.74, 126.31, 122.51, 121.82, 116.12, 113.04, 48.63; HRMS calcd for C25H16Cl3N4O3 [M + H]+ 525.0282, found 525.0283.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(4-bromophenyl)benzamide13k. Yellow solid, yield 63.8%, HPLC 91.72%, m.p. 263–264 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.47 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.73–7.68 (m, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.49 (s, 1H), 6.20 (d, J = 7.8 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 175.99, 175.96, 167.84, 165.11, 144.58, 143.59, 138.72, 136.84, 136.09, 135.01, 131.90, 131.28, 130.57, 130.06, 129.87, 126.78, 126.74, 126.31, 122.87, 121.83, 116.12, 113.04, 48.63; HRMS calcd for C25H16Cl2BrN4O3 [M + H]+ 568.9777, found 568.9778.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(4-iodophenyl)benzamide13l. Yellow solid, yield 64.8%, HPLC 90.03%, m.p. 257–259 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.46 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.74–7.68 (m, 3H), 7.61 (d, J = 8.4 Hz, 2H), 7.51 (s, 1H), 6.20 (d, J = 7.8 Hz, 1H), 6.03 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 175.98, 167.83, 165.11, 144.60, 143.58, 139.20, 137.76, 136.86, 136.11, 135.00, 131.28, 130.57, 130.08, 126.76, 126.30, 123.13, 121.81, 116.12, 113.03, 88.10, 48.64; HRMS calcd for C25H16Cl2IN4O3 [M + H]+ 616.9639, found 616.9642.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(2,4-dimethylphenyl)benzamide13m. Yellow solid, yield 66.6%, HPLC 94.60%, m.p. 211–214 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.12–8.05 (m, 2H), 7.89 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.50 (s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.20 (d, J = 7.8 Hz, 1H), 6.03 (s, 2H), 2.28 (s, 3H), 2.18 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 175.97, 175.94, 167.90, 164.93, 144.58, 143.61, 136.83, 136.08, 135.75, 135.00, 134.02, 133.98, 131.32, 131.13, 130.30, 130.05, 127.01, 126.83, 126.73, 126.28, 121.83, 116.15, 113.04, 48.64, 20.99, 18.23; HRMS calcd for C27H21Cl2N4O3 [M + H]+ 519.0985, found 519.0986.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(2,6-dimethylphenyl)benzamide13n. Yellow solid, yield 63.5%, HPLC 95.45%, m.p. 227–228 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.51 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 8.09–8.06 (m, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.13 (s, 3H), 6.20 (d, J = 7.9 Hz, 1H), 6.04 (s, 2H), 2.18 (s, 6H); 13C-NMR (126 MHz, DMSO-d6) δ 175.95, 167.89, 164.65, 144.57, 143.59, 136.83, 136.00, 135.87, 135.46, 135.00, 130.98, 130.34, 130.13, 129.88, 128.21, 127.25, 126.76, 126.72, 126.38, 121.82, 116.14, 113.03, 48.63, 18.47; HRMS calcd for C27H21Cl2N4O3 [M + H]+ 519.0985, found 519.0983.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-chloro-2-methylph-enyl)benzamide13o. Yellow solid, yield 49.8%, HPLC 93.20%, m.p. 241–244 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.20 (d, J = 7.9 Hz, 1H), 6.03 (s, 2H), 2.23 (s, 3H); 13C-NMR (126 MHz, DMSO-d6) δ 176.04, 175.93, 167.84, 165.13, 144.60, 143.63, 138.26, 136.83, 135.62, 134.99, 134.28, 132.71, 131.27, 130.59, 130.16, 127.38, 126.86, 126.74, 126.38, 121.83, 116.17, 113.04, 99.99, 48.64, 15.77; HRMS calcd for C26H18Cl3N4O3 [M + H]+ 539.0439, found 539.0446.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(3,4-dichlorophenyl)benzamide 13p. Yellow solid, yield 51.4%, HPLC 94.83%, m.p. 265–269 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.47 (s, 1H), 8.17–8.10 (m, 3H), 8.08 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.77–7.69 (m, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 7.8 Hz, 1H), 6.04 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.02, 175.96, 167.79, 165.30, 144.59, 143.58, 139.46, 136.84, 135.72, 135.00, 131.34, 130.99, 130.79, 130.14, 126.77, 126.74, 126.36, 125.87, 122.09, 121.82, 120.85, 116.13, 113.04, 48.64; HRMS calcd for C25H15Cl4N4O3 [M + H]+ 558.9893, found 558.9899.
3-(5-(((5,7-dichloroquinolin-4-yl)oxy)methyl)-1,2,4-oxadiazol-3-yl)-N-(2,4-difluorophenyl)benzamide 13q. Brown solid, yield 47.9%, HPLC 93.53%, m.p. 235–237 °C; 1H-NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.50 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.63–7.56 (m, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.40–7.33 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.20 (d, J = 7.9 Hz, 1H), 6.03 (s, 2H); 13C-NMR (126 MHz, DMSO-d6) δ 176.00, 175.97, 167.82, 165.14, 159.30 (d, J = 11.5 Hz), 157.55 (d, J = 12.8 Hz), 155.56 (d, J = 12.7 Hz), 144.60, 143.58, 136.85, 135.17, 134.99, 131.33, 130.75, 130.17, 129.00 (d, J = 12.2 Hz), 126.84, 126.74, 126.35, 121.81, 116.12, 113.03, 111.70 (d, J = 18.6 Hz), 104.85, 48.65; HRMS calcd for C25H15Cl2F2N4O3 [M + H]+ 527.0484, found 527.0487.

3.3. Biological Activity and Toxicity Determination

The fungicidal activities were investigated in the National Pesticide Engineering Research Center, Nankai University, according to reference [25], and the results of the activity test are shown in Table 2. The toxicity was determined according to Ref. [26].
Through acute exposure, we assessed the toxicity of compound 13p on zebrafish embryo. According to the preliminary exposure experiments, a series of gradient concentrations of compound 13p was set on the basis of mortality rates in the range of 10–95%. LC50 values for zebrafish embryos exposed to compound 13p from 24 to 96 hpf: control (0 mg/L of 13p), 5, 10, 20 mg/L of 13p. The LC50 (median lethal concentration) values were computed by the Boltzmann equation [26,27]. The observational indexes included mortality rate and teratogenic effects.

4. Conclusions

In conclusion, a total of 17 novel benzamides containing quinoline-linked 1,2,4-oxadiazole moiety were designed using splicing principle of active substructures and synthesized via Williamson ether synthesis. The structures of target compounds were confirmed by 1H NMR, 13C NMR, and HRMS. The bioassay results showed that 13a–13q displayed certain inhibitory activity against 10 fungi tested, especially 13f and 13p. It is worth mentioning that the fungicidal activities of 13f and 13p to Sclerotinia sclerotiorum were better than quinoxyfen (14.19 mg/L) with EC50 of 6.67 mg/L and 5.17 mg/L, and their inhibition rates were equal (77.8%) or higher (86.1%) than quinoxyfen (77.8%) at 50 mg/L. Moreover, the acute toxicity of 13p was 19.42 mg/L, which was classified as a low-toxic compound. Hence, these compounds could potentially be lead compounds for further study.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27123946/s1. Figures S1–S17: 1H-NMR spectra of 13a–q; Figures S18–S34: 13C-NMR spectra of 13a–q; Figures S35–S51: ESI-HRMS spectra of 13a–q.

Author Contributions

B.-L.S., Y.-Y.W., S.Y., M.-T.T., Y.-Y.S., Y.H., Y.Z. carried out experimental work, B.-L.S. prepared the manuscript, C.-X.T. designed the material and supervised the project. C.-X.T. revised the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Wynca Group and Siga Co. Ltd. R&D Program, grant numbers KYY-HX-20200138 and KYY-HX-20210049.

Institutional Review Board Statement

The animal study protocol was approved by the Institutional Animal Care and Use Committee (IACUC) at Wenzhou Medical University (SYXK 2019-0009, 4 April 2019 to 4 April 2024).

Acknowledgments

We acknowledge Hui-Li Wang for support with the toxicity determination.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 27 03946 g001 550
Figure 1. Chemical structures of quinoxyfen, ipflufenoquin, quinmerac, tioxazafen and oxolamine.
Figure 1. Chemical structures of quinoxyfen, ipflufenoquin, quinmerac, tioxazafen and oxolamine.
Molecules 27 03946 g001
Molecules 27 03946 g002 550
Figure 2. Design strategy of the target compounds.
Figure 2. Design strategy of the target compounds.
Molecules 27 03946 g002
Molecules 27 03946 sch001 550
Scheme 1. Synthetic route of target compounds. Reagents and conditions: (a) MSA, 60 °C; (b) CH3OH, OH−, 60 °C; (c) PPA, 150 °C; (d) MeCN, H2SO4, K2S2O8, reflux; (e) CH3OH, H+, reflux; (f) CuCN, l-proline, DMF, 100 °C; (g) NH2OH·HCl, CH3CH2OH, rt; (h) ClCH2COCl, Et3N, toluene, reflux; (i) CH3COOH, HCl, 70 °C; (j) SOCl2, reflux; THF, Et3N, 0 °C; (k) K2CO3, DMF, 60 °C.
Scheme 1. Synthetic route of target compounds. Reagents and conditions: (a) MSA, 60 °C; (b) CH3OH, OH−, 60 °C; (c) PPA, 150 °C; (d) MeCN, H2SO4, K2S2O8, reflux; (e) CH3OH, H+, reflux; (f) CuCN, l-proline, DMF, 100 °C; (g) NH2OH·HCl, CH3CH2OH, rt; (h) ClCH2COCl, Et3N, toluene, reflux; (i) CH3COOH, HCl, 70 °C; (j) SOCl2, reflux; THF, Et3N, 0 °C; (k) K2CO3, DMF, 60 °C.
Molecules 27 03946 sch001
Molecules 27 03946 sch002 550
Scheme 2. Hydrolysis reaction of compound 10 under alkaline condition.
Scheme 2. Hydrolysis reaction of compound 10 under alkaline condition.
Molecules 27 03946 sch002
Molecules 27 03946 g003 550
Figure 3. Zebrafish embryo mortality rates after exposure to 13p.
Figure 3. Zebrafish embryo mortality rates after exposure to 13p.
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Molecules 27 03946 g004 550
Figure 4. Zebrafish embryo malformation after exposure to compound 13p. Note: BS, bent spine; PC, pericardial cyst; YC, yolk cyst.
Figure 4. Zebrafish embryo malformation after exposure to compound 13p. Note: BS, bent spine; PC, pericardial cyst; YC, yolk cyst.
Molecules 27 03946 g004
Table
Table 1. Effects of reaction conditions on the synthesis of compound 5.
Table 1. Effects of reaction conditions on the synthesis of compound 5.
EntryOxidantSolventReaction Time/hYield/%
1H2O2MeCN4/
2MnO2THF1043.5
3K2S2O8/H2SO4MeCN486.5
Table
Table 2. Fungicidal activities of compounds 13a–13q at 50 mg/L.
Table 2. Fungicidal activities of compounds 13a–13q at 50 mg/L.
CompoundsRFungicidal Activities (Inhibition Rate %)
ASGZPOPCSSBCRSFOCAPP
13aH7.13.220.025.075.030.46.311.56.715.4
13b2-CH314.316.16.718.872.221.76.311.513.326.9
13c3-CH321.49.720.09.469.430.46.311.56.711.5
13d4-CH321.49.720.09.475.034.825.015.46.711.5
13e4-t-Bu35.719.433.318.855.617.425.015.413.330.8
13f3-CF321.432.320.018.877.821.76.33.820.015.4
13g2-F21.445.220.018.869.421.78.37.76.734.6
13h3-F14.338.720.031.369.434.84.27.76.738.5
13i4-F21.46.520.034.447.28.710.43.813.338.5
13j4-Cl21.43.26.731.355.630.44.23.86.711.5
13k4-Br35.719.433.318.855.621.739.619.220.026.9
13l4-I35.729.033.331.355.68.735.43.813.319.2
13m2,4-di-CH335.745.220.028.150.017.44.27.720.019.2
13n2,6-di-CH335.725.820.018.858.334.818.87.713.338.5
13o3-Cl-2-CH335.738.733.318.875.030.48.37.720.038.5
13p3-Cl-4-Cl7.148.433.331.386.121.735.411.526.738.5
13q2-F-4-F14.332.320.025.066.713.010.47.713.319.2
quinoxyfen 35.745.246.79.477.830.425.042.333.338.5
Note: Alternaria solani (AS), Gibberella zeae (GZ), Pyricularia oryae (PO), Phytophthora capsica (PC), Sclerotinia sclerotiorum (SS), Botrytis cinerea (BC), Riziocotinia solani (RS), Fusarium oxysporum (FO), Cercospora arachidicola (CA), Physalospora piricola (PP). All the data were determined three times.
Table
Table 3. EC50 of compounds 13f, 13p and quinoxyfen to Sclerotinia sclerotiorum (SS).
Table 3. EC50 of compounds 13f, 13p and quinoxyfen to Sclerotinia sclerotiorum (SS).
Compoundsy = a + bxr2EC50/(mg·L−1)
13fy = 1.0563x + 4.12980.98456.67
13py = 1.0992x + 4.21530.99385.17
quinoxyfeny = 1.5356x + 3.23090.978414.19
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Sun, B.-L.; Wang, Y.-Y.; Yang, S.; Tu, M.-T.; Shao, Y.-Y.; Hua, Y.; Zhou, Y.; Tan, C.-X. Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo. Molecules 2022, 27, 3946. https://doi.org/10.3390/molecules27123946

AMA Style

Sun B-L, Wang Y-Y, Yang S, Tu M-T, Shao Y-Y, Hua Y, Zhou Y, Tan C-X. Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo. Molecules. 2022; 27(12):3946. https://doi.org/10.3390/molecules27123946

Chicago/Turabian Style

Sun, Bin-Long, Ying-Ying Wang, Sen Yang, Min-Ting Tu, Ying-Ying Shao, Yi Hua, Yi Zhou, and Cheng-Xia Tan. 2022. "Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo" Molecules 27, no. 12: 3946. https://doi.org/10.3390/molecules27123946

APA Style

Sun, B. -L., Wang, Y. -Y., Yang, S., Tu, M. -T., Shao, Y. -Y., Hua, Y., Zhou, Y., & Tan, C. -X. (2022). Benzamides Substituted with Quinoline-Linked 1,2,4-Oxadiazole: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo. Molecules, 27(12), 3946. https://doi.org/10.3390/molecules27123946

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