Synthesis, antifungal and antibacterial activity for novel amide derivatives containing a triazole moiety
© Tang et al.; licensee Chemistry Central Ltd. 2013
Received: 10 January 2013
Accepted: 4 February 2013
Published: 12 February 2013
Plant fungi (e.g., Pellicularia sasakii, Gibberella zeae, Fusarium oxysporum, and Cytospora mandshurica and Phytophthora infestans) and bacteria (e.g., Ralstonia solanacearum) are extremely difficult to manage in agricultural production. The high incidence of plant mortality and the lack of effective control methods make P. sasakii and R. solanacearum two of the world’s most destructive plant pathogens. Pathogenic fungi and bacteria are responsible for billions of dollars in economic losses worldwide each year. Thus, we designed an active amide structure and synthesized a series of novel amide derivatives containing a triazole moiety to discover new bioactive molecules and pesticides that can act against fungi and bacteria.
A series of amide derivatives containing a triazole moiety were synthesized. All the obtained compounds were characterized through proton and carbon nuclear magnetic resonance spectroscopy, infrared spectroscopy, and elemental analysis. Preliminary antifungal activity test showed that some of the synthesized compounds exhibited moderate antifungal activity against P. sasakii, G. azeae, F. oxysporum, C. mandshurica, and P. infestans at 50 mg/L. Compound 4u displayed more potent antifungal activity against P. sasakii and G. azeae than hymexazol. Preliminary antibacterial activity results showed that some of the synthesized compounds exhibited high anti-bacterial activity against R. solanacearum at 200 mg/L. Compounds 4m and 4q displayed high antibacterial activity against R. solanacearum, with 71% and 65% inhibitory rates, respectively.
A series of novel amide derivatives containing 1,2,4-triazole moiety were synthesized through the reaction of intermediate 3 with different acyl chlorides and anhydrous potassium carbonates in anhydrous tetrahydrofuran at 50°C, using 2,4-dichloroacetophenoneas as a starting material. The title compounds exhibited high inhibitory effects against P. sasakii, R. solanacearum, and G. azeae.
Since the first synthesis of carboxin by Schmeling and Kulkain in 1966 , amide fungicides have also been used for controlling plant diseases for more than 40 years. Amide derivatives have become a research hot spot in the development of pesticides because of their high-efficiency active features and broad spectrum bioactivities, such as antifungal [11, 12], insecticidal , and herbicidal . Currently, some amide derivatives have been developed and commercialized as pesticides. Mepronil, flutolanil, and tiadinil are known for their ability to protect certain plants from severe diseases and pests (Figure 1). In our recent publications [15, 16], several pyrazole amide derivatives containing a hydrazone moiety have been synthesized and tested for their antifungal activity. The synthesized compounds exhibited antifungal activity against Fusarium oxysporum and Cytospora mandshurica, with inhibitory rates ranging from 40.82% to 50.32%. In addition, some hydrazone derivatives containing a pyridine moiety possessed high antibacterial activity against Ralstonia Solanacearum.1-(2,4-Dichlorophenyl)-3-aryl-2-(1H-1,2,4-triazol-1-yl) prop-2-en-1-one derivatives have been synthesized using aldol condensation between 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethan one and an aryl aldehyde. The better compound showed an antifungal activity level similar to that displayed by hymexazol against Gibberell azeae, F. oxysporum, and C. mandshurica.
The resistance of pathogens toward currently available drug therapies is rapidly becoming a major worldwide problem. Thus, the design of new compounds for resistant fungi and bacteria has become one of the most important areas of antibacterial research to date. Plant fungi (e.g., P. sasakii, G. azeae, F. oxysporum, C. mandshurica, and P. infestans) and bacteria (e.g., R. solanacearum) are extremely difficult to control in agricultural production. Pathogenic fungi and bacteria are responsible for billions of dollars in economic losses worldwide each year. In addition, the application of traditional pesticides is not effective and causes high residue level or negative impact on the environment. Therefore, searching for new antifungal and antibacterial agents remains a daunting task in pesticide science. In current study, we combined the active structure of amide and 1, 2, 4-triazole to design and synthesize a series of novel amide derivatives containing a triazole moiety to discover new bioactive molecules and pesticides that can act against fungi and bacteria. Using 2,4-dichloroacetophenone as a starting material, twenty-two novel analogs of amide containing 1,2,4-triazole were synthesized. All the compounds were unequivocally characterized by infrared (IR) spectroscopy, proton and carbon nuclear magnetic resonance spectroscopy (1H NMR and13C NMR, respectively), and elemental analysis. The biological activity of the compounds against G. azeae, F. oxysporum, C. mandshurica, P. sasakii, and P. infestans were tested. The results showed that most of the synthesized compounds exhibited antifungal activity against G. azeae, F. oxysporum, C. mandshurica, P. sasakii, and P. infestans at 50 mg/L and antibacterial activity against R. solanacearum at 200 mg/L. Compounds 3e and 3g showed high antibacterial activity at 200 mg/L. According to the results of bioassay, compound 4u displayed higher potent antifungal activity against P. sasakii and G. azeae than hymexazol. In addition, compounds 4m and 4q displayed high antibacterial activity against R. solanacearum at 200 mg/L, with 71% and 65% inhibitory rates, respectively. To the best of our knowledge, this study is the first to report on the antibacterial activity of amide derivatives containing a 1,2,4-triazole moiety.
Results and discussion
Yields of compound 4i at different reaction conditions
Acid binding agent
Additional file 2 provides the structure, yield, and elemental analysis data for the title compounds.
The structures of the synthesized compounds were confirmed by elemental analysis and 1H-NMR, 13C-NMR, and IR spectroscopy. The IR spectral data of compounds 4a to 4v showed characteristic absorption bands of NH at 3088 cm-1to 3444 cm-1. The absorption bands of the carbonyl and C=C groups of α, β-unsaturated carbonyl skeleton appeared at 1690 cm-1 to 1630 cm-1 and 1530 cm-1 to 1560 cm-1, respectively. In the 1H-NMR spectra of the title compounds, most phenyl protons showed multiple at 6.87 ppm to 8.38 ppm. Notably, the phenyl protons of compound 4p at 9.01 and 9.12 ppm appeared as a singlet because of the existence of two nitro groups in the 3,5-position of the benzene ring, which led to its chemical shift moving to a lower field. The compounds showed the NH proton at 10.53 ppm to 11.07 ppm as a broad singlet. The two protons of the triazole ring appeared at 8.07 ppm to 8.74 ppm and 7.97 ppm to 8.35 ppm. The Ar-OH proton appeared as a broad singlet at 12.07 ppm to 11.44 ppm, and the methyl (Ar-CH3) proton signals were observed as a singlet near 2.18 ppm to 2.34 ppm.
Biological activity and structure-activity relationship (SAR)
Antifungal activity of title compounds 4a to 4v at a concentration of 50 mg/L
Antibacterial activity of compounds 4a to 4v against R. solanacearum
Inhibition rate (%)a
Melting points were determined using a XT-4 binocular microscope (Beijing Tech Instrument Co., Beijing, China) and uncorrected. 1H and 13C-NMR spectra were recorded on a JEOL-ECX 500 NMR spectrometer operating at 500 MHz for 1H-NMR and 125 MHz for 13 C-NMR at room temperature using DMSO-d6 as a solvent and tetramethylsilane as an internal standard. IR spectra were recorded in KBr on an IR Pristige-21 spectrometer (Shimadzu Corporation, Japan). Elemental analysis was performed using an Elemental Vario-III CHN analyzer. Analytical thin layer chromatography was performed on silica gel GF254. Unless otherwise stated, all reagents and reactants were purchased from commercial suppliers and were of analytical grade or chemically pure. All anhydrous solvents were dried and purified according to standard techniques before use. 2-Bromo-1-(2,4-dichlorophenyl) ethanone, intermediate 2, and sodium-1,2,4-triazolide were prepared according to previously reported methods [18, 19] and used without further purification (Additional file 3).
Antifungal biological assay
where C represents the diameter of fungal growth on untreated PDA, T represents the diameter of fungi on treated PDA, and I is the inhibitory rate.
Antibacterial Biological Assay
Where A0 and A1represent the corrected optical density values of the control medium of bacilli and the toxic medium, respectively.
In summary, a series of novel amide derivatives containing a triazole moiety were designed and synthesized through the reaction of intermediate 3 with different acyl chlorides and anhydrous potassium carbonates in THF at room temperature using 2,4-dichloroacetophenone as a starting material. All the prepared compounds were characterized by spectral data (1H-NMR, 13C-NMR, and IR) and elemental analysis. The fungicidal activities in vitro of the compounds against G. azeae, F. oxysporum, C. mandshurica, P. sasakii, and P. infestans were evaluated. The results showed that the title compounds possessed low to high antifungal activities against the tested fungi. Compound 4u displayed high antifungal activity. Furthermore, the antibacterial tests indicated that some of the synthesized compounds also possessed moderate activity against R. solanacearum. Compounds 4b, 4m, and 4q exhibited high inhibitory activity against tobacco bacterial wilts in vitro. The results of preliminary SAR study indicated that the fungicidal activity can be decreased by introduction of hydroxyl at the 2-position of the benzene ring, the compound containing a furan displayed higher antifungal activity against different fungi than that of benzene, and the substituent of 2,4-di-fluoro on the phenyl ring can enhance the activities against G. azeae. However, unlike antifungal activity, the free hydroxyl group at the 2-position of the benzene plays an important role in the antibacterial activity against R. solanacearum, and the compounds containing 2,4-dicloro showed much higher activity than that of 2,4-difluro, and the introduction of heterocyclic ring could decrease the antibacterial activity. Moreover, the methoxy at the 2-position of the benzene ring also improved the antibacterial activity. Further studies are currently underway to establish a definite SAR.
This study is financially supported by the National Natural Science Foundation of China (No. 20962005) and Key Technologies R&D Program (No.2011BAE06B05-6).
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