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[email protected] Letters in Drug Design & Discovery, 2016, 13, 521-525 ISSN: 1570-1808 eISSN: 1875-628X
Microwave Assisted Synthesis and Antifungal Activity of Some Novel Thioethers Containing 1,2,4-triazolo[4,3-a] pyridine Moiety
Volume 13, Number 6
Impact Factor: 0.77
BENTHAM SCIENCE
Zhi-Wen Zhai1,§, Yan-Xia Shi2,§, Ming-Yan Yang1, Wen Zhao1, Zhao-Hui Sun1, Jian-Quan Weng1, Cheng-Xia Tan1, Xing-Hai Liu1,*, Bao-Ju Li2,* and Yong-Gang Zhang3,* 1
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, China
Letters in Drug Design & Discovery
2
Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing, 100014, China 3
Biology Institute of Shandong Academy of Science, Jinan, 250014, China Abstract: A novel series of novel 1,2,4-triazolo[4,3-a]pyridines were designed and synthesized under microwave irradiation condition. The structures were identified by 1H NMR, MS and elemental analysis, and the antifungal activities of them were evaluated at 100 ppm. It was found that some of the 1,2,4-triazolo[4,3-a]pyridines displayed good antifungal activity. Among them, compound 2e exhibited good antifungal activity against Stemphylium lycopersici (Enjoji) Yamamoto and Fusarium oxysporum. Sp. Cucumebrium.
Xing-Hai Liu
Keywords: 1,2,4-triazolo[4,3-a]pyridine, antifungal activities, microwave assisted synthesis, thioether. Received: April 29, 2015
Revised: September 09, 2015
INTRODUCTION Nowadays, the fungicide-resistance problem has become a serious one throughout the world. It is important to discover novel structures with new interaction mechanism or new target in order to overcome these problems [1, 2]. 1,2,4Triazoles are a classic heterocycles in medicines, agricultures or industry. They displayed antiproliferative activity [3], anticonvulsant activity [4], fungicidal activity [5], anticancer activity [6] and can act as P-glycoprotein-mediated multidrug resistance Inhibitors [7]. They can also be used for the control weeds [8]. Some of them had been developed to commercial pesticides [9-11], such as azafenidin, amicarbazone, sulfentrazone and so on (Fig. 1). Another important nitro-containing heterocycle—pyridine which showed various bioactivities [12-15]. For instances, the commercial herbicides diflufenzopyr, dithiopyr or Nicosulfuron contain pyridine ring. (Fig. 1) Several reports have found diverse applications for 1,2,4-triazolo[4,3-a]pyridine, such as mGlu2 receptor PAM activity [16], anticonvulsant activity [17], antibacterial agent [18], antimicrobial activity [19], herbicidal activity [20] and so on. Therefore, the synthesis of versatile structures for 1,2,4-triazolo[4,3-a]pyridine is of interest to chemists. In our previous work, some interesting 1,2,4-triazoles were synthesized and they showed various activities [21-34]. In order to explore the potential antifungal activity of fused 1,2,4-triazole derivatives, especially 1,2,4-triazolo[4,3*Address correspondence to this author at the College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China; Tel/Fax: +86 571 88320832; E-mails:
[email protected];
[email protected];
[email protected] §
These authors contributed equally
1875-628X/16 $58.00+.00
Accepted: September 18, 2015
a]pyridine derivatives, a novel series of 1,2,4-triazolo[4,3a]pyridines were designed and synthesized under microwave irradiation condition. The antifungal activities of 1,2,4triazolo[4,3-a]pyridine derivatives were evaluated in vivo. The results of antifungal activity indicated that some compounds displayed significant antifungal activity. RESULTS AND DISCUSSION Synthesis and Spectra The synthesis procedures of 1,2,4-triazolo[4,3a]pyridines were outlined in Scheme (1). The start material 3-chloro-2-hydrazinylpyridine was prepared in our lab. The key intermediate 8-chloro-[1,2,4]triazolo[4,3-a]pyridine3(2H)-thione was synthesized under microwave irradiation condition. Referring to the literature reported by Chen[35] for the synthesis of trazodone hydrochloride, 1,2,4triazolo[4,3-a]pyridin-3(2H)-one was prepared successfully using solid phase synthesis method. In our synthetic process, microwave irradiation method was used. According to this method, the key intermediate 8-chloro-[1,2,4]triazolo[4,3a]pyridine-3(2H)-thione was obtained involving 3-chloro-2hydrazinylpyridine with thiourea. Then the reactions of intermediate 1 with alkyl halides or substituted benzyl halides in water under microwave irradiation in the presence of NaOH as base gave the corresponding compounds 2. The 1 H NMR data indicated that the substitution of 8-chloro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-thione occurred at sulfur atom but not nitrogen atom, as expected for thiol. The CH2 protons between the triazole ring and benzene ring arose at around 5.0 ppm. This is consistent with the reference [36]. Compounds 2a~2k were identified by 1H NMR, MS, X-ray single crystal or elemental analysis. The 1H NMR spectra of
©2016 Bentham Science Publishers
522 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Zhai et al.
N N
N
NH2
O
O
H N
Cl
F
N N
O amicarbazone
Cl
O Cl
OH
O
F
F
F
diflufenzopyr
S S
F N H
O O
O
S
O
H N
O
O HN
N
F
N F
O S
sulfentrazone N
N H
H N
F
N
O
N
N O
Cl
azafenidin
N
N N
N
O
N
F dithiopyr
Nicosulfuron
O
Fig. (1). Some representative commercial herbicides containing 1,2,4-triazole ring or pyridine ring. Cl
Cl Cl
RX, NaOH
Thiourea N
N H
NH2
N
MW
N
N DMF, MW
N N
NH
S
S
R 1
2
Scheme (1). The synthetic route of title compounds.
compounds 2a~2k have been recorded in CDCl3. Among the significant feature of 1H NMR data of compound 2, the singlet at 6.22 (SH in triazole ring) was disappeared in the key intermediate 1 respectively. The CH proton signals of pyridine structure of compound 2a~2k were obvious at 6.627.00, 7.02-7.51, 7.31-7.82 ppm respectively. The signal of CH2 proton appeared around at 3.77-5.30 ppm. The elemental analyses and MS results showed that it is consistent with the calculated values. Antifungal Activity The antifungal activities of compound 2a~2k were tested in a greenhouse at a dosage of 100 ppm against Stemphylium lycopersici (Enjoji) Yamamoto (SL), Fusarium oxysporum. Sp. Cucumebrium (FO) and Botrytis cinerea (BC). From Table 1, most of the compounds, especially compounds 2c, 2d, 2e, 2h, 2i, 2k were found to display good antifungal activity against Stemphylium lycopersici (Enjoji) Yamamoto. For instance, compound 2c exhibited 80.65% inhibition against Stemphylium lycopersici (Enjoji) Yamamoto. Compound 2d also displayed good inhibition antifungal activities against Stemphylium lycopersici (Enjoji) Yamamoto (74.85%), Fusarium oxysporum. Sp. Cucumebrium (83.33%) respectively. For the compound 2e, it exhibited excellent inhibitory activities against Fusarium oxysporum. Sp. Cucumebrium (84.26%), but it displayed moderate activity against Stemphylium lycopersici (Enjoji) Yamamoto(56.85%). For the Fusarium oxysporum. Sp. Cucumebrium, most of title compounds exhibited moderate activity (about 50%), except compound 2d and 2e. Unfortunately, most of 1,2,4-triazolo[4,3-a]pyridines exhibited weak antifungal activities against Botrytis cinerea.
Table 1. The antifungal activities of title compounds. No.
SL
FO
BC
2a
26.34
62.73
12.64
2b
20.24
51.11
18.89
2c
80.65
40.56
21.11
2d
74.85
83.33
24.26
2e
56.85
84.26
18.89
2f
16.67
72.22
24.26
2g
34.52
71.11
28.89
2h
53.87
48.89
0.00
2i
56.25
49.44
5.56
2j
4.17
45.28
6.67
2k
51.19
62.02
15.56
zhongshengmycin
59.58
Thiophanate-Methyl Cyprodynil
81.69 45.56
CONCLUSION In summary, we had successfully designed and synthesized a novel series of 1,2,4-triazolo[4,3-a]pyridine deriva-
Microwave Assisted Synthesis
tives. The easy and practice method “microwave irradiation” was used. Their structures were confirmed by 1H NMR, elemental analyses and MS. Furthermore the antifungal activity was investigated, the results indicated that some compounds exhibited good antifungal activity. EXPERIMENT Instrument All the chemical reagents are of analytical grade or prepared by our lab. Melting points were measured using an X4 apparatus and were uncorrected. 1H NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer using CDCl3 as solvent. Mass spectra were determined on a Thermo Finnigan LCQ Advantage LC/mass detector instrument. Elemental analysis data of title compounds were collected by a Perkin-Elmer 240C analyzer. CEM Discover Focused Synthesizer was used to carry out the microwave reaction. General Procedure Preparation of 2a: The 3-chloro-2-hydrazinylpyridine (143 mg, 1mmol) and thiourea (3 mmol) were exposed to CEM Discover Focused Synthesizer at 180 °C for 30 min. Then the mixture was poured into water (40 mL), filtered and recrystallized to give the key intermediate 8-chloro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-thione. 1H NMR (CDCl3, 400 MHz), : 6.22(s, 1H, SH), 6.66(t, J=5.0Hz, 1H, Py-H), 7.48(d, J=7.6Hz, 1H, Py-H), 8.11(d, J=4.9Hz, 1H, Py-H). 8Chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)- thione (1mmol), DMF (5 mL), RCH2 Cl (1.1 mmol) and NaOH (0.05 g, 1.2mmol) was irradiated at 90°C for 15 min. After the reaction is completed, the mixture was poured into crushed ice and the target compound 2a was collected, recrystallized. The crude product was purified by column chromatography. The other compounds 2b~2k were synthesized using the same method. 3-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine 2a yield 87%, m.p.140-141; 1H NMR (CDCl3, 400 MHz), : 4.29 (s, 2H, SCH2), 6.62(t, J=7.0Hz, 1H, Py-H), 7.097.11(m, 2H, Ar-H), 7.15-7.16(m, 3H, Py-H and Ar-H), 7.27(s, 1H, Ar-H), 7.62(d, J=6.8Hz, 1H, Py-H). ESI-MS: 276[M+H]+; Elemental analysis for C13H10ClN3S: found C 56.74, H 3.76, N 15.43; calcd. C, 56.62; H, 3.66; N, 15.24. 8-chloro-3-((3,4-dichlorobenzyl)thio)[1,2,4]triazolo[4,3-a]pyridine 2b yield 81%, m.p.152-153; 1 H NMR (CDCl3, 400 MHz), : 4.30 (s, 2H, SCH2), 6.75(t, J=7.0Hz, 1H, Py-H), 7.02(d, J=6.2Hz, 1H, Py-H), 7.33(d, J=6.5Hz, 1H, Py-H). ESI-MS: 345[M+H]+; Elemental analysis for C13H8Cl3N3S: found C 45.44, H 2.53, N 11.98; calcd. C, 45.30; H, 2.34; N, 12.19. methyl methyl 2-(2-(((8-chloro-[1,2,4]triazolo[4,3a]pyridin-3-yl)thio)methyl)phenyl)-2-(methoxyimino)acetate 2c yield 77%, m.p.155-156; 1H NMR (CDCl3, 400 MHz), : 3.77(s, 3H, OCH3), 3.89(s, 3H, OCH3), 4.10 (s, 2H, SCH2), 6.53(t, J=7.0Hz, 1H, Py-H), 6.66(d, J=7.0Hz, 1H, ArH), 6.90(d, J=7.5Hz, 1H, Ar-H), 7.13(d, J=7.5Hz, 1H, ArH), 7.19(t, J=7.5Hz, 1H, Ar-H), 7.25(d, J=7.0Hz, 1H, Py-H),
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7.71(d, J=6.9Hz, 1H, Py-H). ESI-MS: 412[M+Na]+; Elemental analysis for C17H15ClN4O3S: found C 52.33, H 3.97, N 14.45; calcd. C, 52.24; H, 3.87; N, 14.33. 2-((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3yl)thio)acetonitrile 2d yield 68%, m.p.200-201°C; 1H NMR (CDCl3, 400 MHz), : 3.90 (s, 2H, SCH2), 7.00(t, J=7.0Hz, 1H, Py-H), 7.48(d, J=7.2Hz, 1H, Py-H), 7.24-7.28(m, 2H, Ar-H), 7.31(d, J=6.5Hz, 1H, Py-H), 7.31(d, J=6.8Hz, 1H, Py-H). ESI-MS: 225[M+H]+; Elemental analysis for C8H5ClN4S: found C 42.97, H 2.31, N 24.99; calcd. C, 42.77; H, 2.24; N, 24.94. 4-(((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3yl)thio)methyl)benzonitrile 2e yield 76%, m.p.194-195°C; 1 H NMR (CDCl3, 400 MHz), : 4.50 (s, 2H, SCH2), 6.89(t, J=7.0Hz, 1H, Py-H), 7.40(d, J=8.1Hz, 1H, Ar-H), 7.45(d, J=6.5Hz, 1H, Py-H), 7.54(d, J=8.1Hz, 1H, Ar-H), 7.82(d, J=6.8Hz, 1H, Py-H). ESI-MS: 301[M+H]+; Elemental analysis for C14H9ClN4S: found C 55.89, H 2.97, N 18.87; calcd. C, 55.91; H, 3.02; N, 18.63. 8-chloro-3-(((6-chloropyridin-3-yl)methyl)thio)[1,2,4]triazolo[4,3-a]pyridine 2f yield 82%, m.p.150-151°C; 1 H NMR (CDCl3, 400 MHz), : 4.40 (s, 2H, SCH2), 6.81(t, J=7.0Hz, 1H, Py-H), 7.18(d, J=8.2Hz, 1H, Py-H), 7.34(d, J=7.2Hz, 1H, Py-H), 7.58(dd, J=2.5, 2.5Hz, 1H, Py-H), 7.78(d, J=6.9Hz, 1H, Py-H), 8.31(d, J=2.3Hz, 1H, Py-H). ESI-MS: 311[M+H]+; Elemental analysis for C12H8Cl2N4S: found C 46.42, H 2.75, N 17.96; calcd. C, 46.32; H, 2.59; N, 18.00. 8-chloro-3-((3-fluorobenzyl)thio)-[1,2,4]triazolo[4,3a]pyridine 2g yield 81%, m.p.99-100°C; 1H NMR (CDCl3, 400 MHz), : 4.30 (s, 2H, SCH2), 6.69(t, J=7.0Hz, 1H, PyH), 6.85-6.91(m, 2H, Ar-H), 6.93(d, J=1.6Hz, 1H, Ar-H), 7.09-7.13(m, 1H, Ar-H), 7.27(d, J=7.2Hz, 1H, Py-H), 7.71(d, J=7.5Hz, 1H, Py-H). ESI-MS: 294[M+H]+; Elemental analysis for C13H9ClFN3S: found C 53.22, H 2.97, N 14.51; calcd. C, 53.15; H, 3.09; N, 14.30. 8-chloro-3-((2-chlorobenzyl)thio)-[1,2,4]triazolo[4,3a]pyridine 2h yield 79%, m.p.152-153°C; 1H NMR (CDCl3, 400 MHz), : 4.42 (s, 2H, SCH2), 6.67(t, J=7.0Hz, 1H, PyH), 6.97(d, J=4.0Hz, 2H, Ar-H), 7.13-7.17(m, 1H, Ar-H), 7.27-7.29(m, 1H, Ar-H), 7.34(d, J=7.9Hz, 1H, Py-H), 7.72(d, J=6.9Hz, 1H, Py-H). ESI-MS: 312[M+H]+; Elemental analysis for C13H9Cl2N3S: found C 50.46, H 2.90, N 13.64; calcd. C, 50.33; H, 2.92; N, 13.55. 3-((4-bromobenzyl)thio)-8-chloro-[1,2,4]triazolo[4,3a]pyridine 2i yield 89%, m.p.168-169°C; 1H NMR (CDCl3, 400 MHz), : 4.42 (s, 2H, SCH2), 6.72(t, J=6.9Hz, 1H, PyH), 7.04(d, J=7.8Hz, 2H, Ar-H), 7.28-7.33(m, 3H, Ar-H and Py-H), 7.69(d, J=6.9Hz, 1H, Py-H). ESI-MS: 356[M+H]+; Elemental analysis for C13H9BrClN3S: found C 44.33, H2.61, N 11.68; calcd. C, 44.03; H, 2.56; N, 11.85. 3-(((8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3yl)thio)methyl)benzonitrile 2j yield 83%, m.p.186-187°C; 1 H NMR (CDCl3, 400 MHz), : 4.44 (s, 2H, SCH2), 6.82(t, J=6.9Hz, 1H, Py-H), 7.31-7.37(m, 2H, Ar-H), 7.47(d, J=7.8Hz, 1H, Ar-H), 7.51(d, J=7.8Hz, 1H, Py-H), 7.61(s, 1H, Ar-H), 7.80(d, J=6.7Hz, 1H, Py-H). ESI-MS: 310[M+H]+; Elemental analysis for C14H9ClN4S: found C 55.89, H 2.88, N 18.86; calcd. C, 55.91; H, 3.02; N, 18.63.
524 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
8-chloro-3-((4-chlorobenzyl)thio)-[1,2,4]triazolo[4,3a]pyridine 2k yield 81%, m.p.162-163°C; 1H NMR (CDCl3, 400 MHz), : 4.28 (s, 2H, SCH2), 6.69(t, J=7.0Hz, 1H, PyH), 7.06(d, J=8.4Hz, 2H, Ar-H), 7.14(d, J=8.4Hz, 2H, ArH), 7.29(d, J=7.7Hz, 1H, Py-H), 7.67(d, J=7.4Hz, 1H, PyH). ESI-MS: 310[M+H]+; Elemental analysis for C13H9Cl2N3S: found C 50.13, H 3.05, N 13.71; calcd. C, 50.33; H, 2.92; Cl, 22.86; N, 13.55. Antifungal Activities Antifungal activity of 2a~2k against Stemphylium lycopersici (Enjoji) Yamamoto, Fusarium oxysporum. sp. cucumebrium and Botrytis cinerea was determined according to references [37-38], and a potted plant test method was adopted. Germination was conducted by soaking cucumber seeds in water for 2 h at 50 o C and then keeping the seeds moist for 24 h at 28 oC in an incubator. When the radicles were 0.5 cm, the seeds were grown in plastic pots containing a 1:1 (v/v) mixture of vermiculite and peat. Cucumber and tomato plants used for inoculations were at the stage of two seed leaves. Tested compounds and commercial fungicides was sprayed with a hand spray on the surface of the seed leaves on a fine morning, at the standard concentration of 100 g/mL, zhongshengmycin, thiophanate-methyl and cyprodinil were used as a control. After 2 h, inoculations of Stemphylium lycopersici (Enjoji) Yamamoto was carried out by spraying fungal suspension, inoculation of Fusarium oxysporum. sp. cucumebrium was carried out by spraying mycelial suspension, inoculation of Botrytis cinerea was carried out by radicle soaking. The experiment was repeated 4 times. After inoculation, the plants were maintained at 18-30 oC [mean temperature of 24 oC and above 80% relative humidity (RH)]. The fungicidal activity was evaluated when the nontreated cucumber plant (blank) fully manifested symptoms. The area of inoculated treated leaves covered by disease symptoms was assessed and compared to that of nontreated ones to determine the average disease index. The relative control efficacy of compounds compared to the blank assay was calculated via the following equation:
Zhai et al. [2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13]
[14]
relative control efficacy (%)=(CK-PT)/CK 100% [15]
where CK is the average disease index during the blank assay and PT is the average disease index after treatment during testing.
[16]
CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
[17]
ACKNOWLEDGEMENTS This research was supported in part by National Key Technologies R&D Program (2011BAE06B03-01), National Natural Science Foundation of China (No. 21002090). REFERENCES [1]
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Microwave Assisted Synthesis
[20]
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[22]
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[24]
[25]
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