Design, Synthesis and Bioactivity Evaluation of Novel 2-(pyrazol-4-yl)-1,3,4-oxadiazoles Containing an Imidazole Fragment as Antibacterial Agents

Imidazole alkaloids, a common class of five-membered aromatic heterocyclic compounds, exist widely in plants, animals and marine organisms. Because of imidazole’s extensive and excellent biological and pharmacological activities, it has always been a topic of major interest for researchers and has been widely used as an active moiety in search of bioactive molecules. To find more efficient antibacterial compounds, a series of novel imidazole-fragment-decorated 2-(pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized based on our previous works via the active substructure splicing principle, and their bioactivities were systematically evaluated both in vitro and in vivo. The bioassays showed that some of the target compounds displayed excellent in vitro antibacterial activity toward three virulent phytopathogenic bacteria, including Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac) and Pseudomonas syringae pv. actinidiae (Psa), affording the lowest EC50 values of 7.40 (7c), 5.44 (9a) and 12.85 (9a) μg/mL, respectively. Meanwhile, compound 7c possessed good in vivo protective and curative activities to manage rice bacterial leaf blight at 200 μg/mL, with control efficacies of 47.34% and 41.18%, respectively. Furthermore, compound 9a showed commendable in vivo protective and curative activities to manage kiwifruit bacterial canker at 200 μg/mL, with control efficacies of 46.05% and 32.89%, respectively, which were much better than those of the commercial bactericide TC (31.58% and 17.11%, respectively). In addition, the antibacterial mechanism suggested that these new types of title compounds could negatively impact the cell membranes of phytopathogenic bacteria cells and cause the leakage of the intracellular component, thereby leading to the killing of bacteria. All these findings confirm that novel 2-(pyrazol-4-yl)-1,3,4-oxadiazoles containing an imidazole fragment are promising lead compounds for discovering new bactericidal agents.

[1]  Mohammed Aarjane,et al.  Novel triazole derivatives possessing imidazole: Synthesis, spectroscopic characterization (FT-IR, NMR, UV-Vis), DFT studies and antibacterial in vitro evaluation , 2022, Journal of Molecular Structure.

[2]  Xinling Yang,et al.  Design, Synthesis and Fungicidal Activity of N-(thiophen-2-yl) Nicotinamide Derivatives , 2022, Molecules.

[3]  Song Yang,et al.  Novel 1,3,4-Oxadiazole Thioether and Sulfone Derivatives Bearing a Flexible N-Heterocyclic Moiety: Synthesis, Characterization, and Anti-microorganism Activity , 2022, Arabian Journal of Chemistry.

[4]  M. Rahal,et al.  Allylamines, Benzylamines, and Fungal Cell Permeability: A Review of Mechanistic Effects and Usefulness against Fungal Pathogens , 2022, Membranes.

[5]  C. Yamali,et al.  N-Benzoylthiourea-pyrrolidine carboxylic acid derivatives bearing an imidazole moiety: Synthesis, characterization, crystal structure, in vitro ChEs inhibition, and antituberculosis, antibacterial, antifungal studies , 2022, Journal of Molecular Structure.

[6]  L. Yang,et al.  Novel 18β-glycyrrhetinic acid amide derivatives show dual-acting capabilities for control of plant bacterial diseases through ROS-mediated antibacterial efficiency and activation of plant defense responses , 2022, Journal of Integrative Agriculture.

[7]  Muhammad Saeed Khan Jadoon,et al.  Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis , 2022, Molecules.

[8]  Yingying Wei,et al.  Epinecidin-1, a marine antifungal peptide, inhibits Botrytis cinerea and delays gray mold in postharvest peaches. , 2022, Food chemistry.

[9]  Wei Chen,et al.  Synthesis, Antifungal Activity, and 3D-QASR of Novel 1,2,3,4-Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors. , 2022, Journal of agricultural and food chemistry.

[10]  S. H. A. Chen,et al.  A novel ammonium zinc molybdate layered double hydroxide nanoflakes/vapor grown carbon fibers nanomaterials based electrocatalyst for the monitoring of dimetridazole drug in real samples , 2022, Journal of Environmental Chemical Engineering.

[11]  C. Westerhausen,et al.  Shear stress induced lipid order and permeability changes of giant unilamellar vesicles. , 2022, Biochimica et biophysica acta. General subjects.

[12]  Song Yang,et al.  Discovery of novel rost-4-ene derivatives as potential plant activators for preventing phytopathogenic bacterial infection: Design, synthesis, and biological studies. , 2022, Pest management science.

[13]  A. Basaleh,et al.  Theoretical Investigation by DFT and Molecular Docking of Synthesized Oxidovanadium(IV)-Based Imidazole Drug Complexes as Promising Anticancer Agents , 2022, Molecules.

[14]  Xu-Liang Nie,et al.  Design, Synthesis and Bioactivity Evaluation of Coumarin–BMT Hybrids as New Acetylcholinesterase Inhibitors , 2022, Molecules.

[15]  Lingmei Fu,et al.  Determination of Cyazofamid and Its Metabolite in Oily Agricultural Products with HPLC-MS/MS. , 2022, Journal of chromatographic science.

[16]  Vasyl Kovalishyn,et al.  Design of new imidazole derivatives with anti-HCMV activity: QSAR modeling, synthesis and biological testing , 2021, Journal of Computer-Aided Molecular Design.

[17]  Aiping Lu,et al.  ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties , 2021, Nucleic Acids Res..

[18]  Liwei Liu,et al.  Rational Optimization of 1,2,3-Triazole-Tailored Carbazoles As Prospective Antibacterial Alternatives with Significant In Vivo Control Efficiency and Unique Mode of Action. , 2021, Journal of agricultural and food chemistry.

[19]  C. Lamberth.  Imidazole Chemistry in Crop Protection , 2021 .

[20]  F. Wang,et al.  Antibacterial Functions and Proposed Modes of Action of Novel 1,2,3,4-Tetrahydro-β-carboline Derivatives that Possess an Attractive 1,3-Diaminopropan-2-ol Pattern against Rice Bacterial Blight, Kiwifruit Bacterial Canker, and Citrus Bacterial Canker. , 2020, Journal of agricultural and food chemistry.

[21]  Mohamed El Mehdi Mekhzoum,et al.  Recent Advances in the Synthesis and Applications of Thiabendazole Derivatives: A Short Review , 2020, Current Organic Chemistry.

[22]  Liwei Liu,et al.  Synthesis of Thiazolium-Labeled 1,3,4-Oxadiazole Thioethers as Prospective Antimicrobials: In Vitro and In Vivo Bioactivity and Mechanism of Action. , 2019, Journal of agricultural and food chemistry.

[23]  Qing-Su Long,et al.  Identification of Racemic and Chiral Carbazole Derivatives Containing an Isopropanolamine Linker as Prospective Surrogates Against Plant Pathogenic Bacteria: In Vitro and In Vivo Assays, and Quantitative Proteomics. , 2019, Journal of agricultural and food chemistry.

[24]  Dan Zeng,et al.  Rational Optimization and Action Mechanism of Novel Imidazole (or Imidazolium)-Labeled 1,3,4-Oxadiazole Thioethers as Promising Antibacterial Agents against Plant Bacterial Diseases. , 2019, Journal of agricultural and food chemistry.

[25]  Zhanyong Guo,et al.  Enhanced antioxidant and antifungal activity of chitosan derivatives bearing 6-O-imidazole-based quaternary ammonium salts. , 2019, Carbohydrate polymers.

[26]  Ming Sun,et al.  Isolation and characterization of a novel phage Xoo-sp2 that infects Xanthomonas oryzae pv. oryzae. , 2018, The Journal of general virology.

[27]  Song Yang,et al.  Antimicrobial activities of pyridinium-tailored pyrazoles bearing 1,3,4-oxadiazole scaffolds , 2017 .

[28]  G. Bifulco,et al.  Tulongicin, an Antibacterial Tri-Indole Alkaloid from a Deep-Water Topsentia sp. Sponge. , 2017, Journal of natural products.

[29]  S. Madhuri,et al.  Synthesis and Antiviral Activity of Sulfonohydrazide and 1,3,4-Oxadiazole Derivatives of 6,6-Dimethyl-9-Oxo-4,5,6,7,8,9-Hexahydropyrazolo[5,1-b] Quinazoline , 2017 .

[30]  S. A. El‐Hawash,et al.  New benzothiophene derivatives as dual COX-1/2 and 5-LOX inhibitors: synthesis, biological evaluation and docking study. , 2017, Future medicinal chemistry.

[31]  M. S. Bhullar,et al.  Weed control in conventional soybean with pendimethalin followed by imazethapyr + imazamox/quizalofop-p-ethyl , 2017, Canadian Journal of Plant Science.

[32]  Pei-Yi Wang,et al.  Antibacterial and Antifungal Activities of 2‐(substituted ether)‐5‐(1‐phenyl‐5‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl)‐1,3,4‐oxadiazole Derivatives , 2017 .

[33]  W. Shi,et al.  Morphological and physiological changes induced by contact-dependent interaction between Candida albicans and Fusobacterium nucleatum , 2016, Scientific Reports.

[34]  A. Rico,et al.  Lethal and sub-lethal effects of five pesticides used in rice farming on the earthworm Eisenia fetida. , 2016, Ecotoxicology and environmental safety.

[35]  Dipak K. Raval,et al.  Design, synthesis, and characterization of a fluoro substituted novel pyrazole nucleus clubbed with 1,3,4-oxadiazole scaffolds and their biological applications , 2016 .

[36]  Dinesh Kumar,et al.  Influence of Co-Administration of Parbendazole on The Disposition Kinetics and Efficacy of Albendazole in Goats , 2016 .

[37]  W. Mu,et al.  Baseline sensitivity and efficacy of the sterol biosynthesis inhibitor triflumizole against Botrytis cinerea , 2016, Australasian Plant Pathology.

[38]  F. Zhu,et al.  A Comparison of Different Estimation Methods for Fungicide EC 50 and EC 95 Values , 2015 .

[39]  M. Kumar,et al.  Synthesis of some pyrazolylaldehyde N-isonicotinoyl hydrazones and 2,5-disubstituted 1,3,4-oxadiazoles as DNA photocleaving agents , 2015, Medicinal Chemistry Research.

[40]  A. E. Rashad,et al.  Studies on the Reactivity of Amino-1-(6-phenyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic Acid Hydrazide Towards Some Reagents for Biological Evaluation , 2014 .

[41]  S. Ningaiah,et al.  Novel pyrazole integrated 1,3,4-oxadiazoles: synthesis, characterization and antimicrobial evaluation. , 2014, Bioorganic & medicinal chemistry letters.

[42]  Ling Zhang,et al.  Comprehensive Review in Current Developments of Imidazole‐Based Medicinal Chemistry , 2014, Medicinal research reviews.

[43]  Chengsheng Zhang,et al.  Synthesis of thiodiazole copper microcapsules and release behavior of inhibiting R. solanacearum , 2014 .

[44]  H. Tingting,et al.  Detection and characterization of bismerthiazol-resistance of Xanthomonas oryzae pv. oryzae , 2013 .

[45]  Cheng-Mei Zhang,et al.  Recent developments of p38α MAP kinase inhibitors as antiinflammatory agents based on the imidazole scaffolds. , 2013, Current medicinal chemistry.

[46]  Zhong Jin.  Muscarine, imidazole, oxazole, and thiazole alkaloids. , 2003, Natural product reports.

[47]  G. Elgemeie,et al.  Synthesis and in vitro anti-tumor activity of new oxadiazole thioglycosides. , 2011, European journal of medicinal chemistry.

[48]  R. Kumar,et al.  Hypervalent iodine(III) mediated synthesis of novel unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles as antibacterial and antifungal agents. , 2010, European journal of medicinal chemistry.

[49]  G. Zhong,et al.  Control of citrus postharvest green and blue mold and sour rot by tea saponin combined with imazalil and prochloraz , 2010 .

[50]  B. Liu,et al.  Screening rules for leads of fungicides, herbicides, and insecticides. , 2010, Journal of agricultural and food chemistry.

[51]  Min Ju Kim,et al.  Pentacycle derivatives as cannabinoid CB1 receptor ligands. , 2009, Bioorganic & medicinal chemistry letters.

[52]  B. Foley,et al.  Rapid confirmatory method for the determination of 11 nitroimidazoles in egg using liquid chromatography tandem mass spectrometry. , 2009, Journal of chromatography. A.

[53]  V. Narayanaswamy,et al.  Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles. , 2009, European journal of medicinal chemistry.

[54]  L. De Luca.  Naturally occurring and synthetic imidazoles: their chemistry and their biological activities. , 2006, Current medicinal chemistry.

[55]  D. B. Duncan.  MULTIPLE RANGE AND MULTIPLE F TESTS , 1955 .