1. Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, College of Life Science, Huzhou University, Huzhou 313000, China 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, China 3. Laboratory of Grassland Agro-ecosystems, Lanzhou University, Lanzhou 730000, China
To ensure the production of food crops, a series of cryptolepine derivatives were synthesised, after which their antibacterial activities and mechanism of action against three plant pathogens were investigated. Our bioassay results indicated that most of the target compounds displayed potent inhibitory effects against Xanthomonas oryzae (X. oryzae) and Xanthomonas axonopodis pv. citri (X. axonopodis pv. c.). Remarkably, compound 9 exhibited the best in vitro antibacterial activity against X. oryzae, with a minimum inhibitory concentration (MIC) value of 0.78 μg·mL–1. Compound 2 exhibited the best in vitro antibacterial activity against X. axonopodis pv. c., with an MIC value of 0.39 μg·mL–1. These activities were superior to those of copper quinolate (MIC = 6.25, 25 μg·mL–1) and thiodiazole copper (MIC = 100, 200 μg·mL–1) against X. oryzae and X. axonopodis pv. c. In vivo experiments demonstrated the promising applicability of compound 9 for the control of rice bacterial infections. Furthermore, compound 9 was selected as a candidate to conduct preliminary analyses of the antibacterial mechanisms of cryptolepine derivatives. Scanning electron microscopy and transmission electron microscopy observations, extracellular polysaccharide production, biofilm formation, transcriptomic, quantitative reverse transcription-polymerase chain reaction analyses, and molecular docking assays were performed. Collectively, our findings demonstrated that compound 9 might act via multifarious mechanisms to down-regulate virulence factors and cause cell death.
P Li, D Hu, D Xie, J Chen, L Jin, B Song. Design, synthesis, and evaluation of new sulfone derivatives containing a 1,3,4-oxadiazole moiety as active antibacterial agents. Journal of Agricultural and Food Chemistry, 2018, 66( 12): 3093– 3100 https://doi.org/10.1021/acs.jafc.7b06061
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P Y Wang, M W Wang, D Zeng, M Xiang, J R Rao, Q Q Liu, L W Liu, Z B Wu, Z Li, B A Song, S Yang. Rational optimization and action mechanism of novel imidazole (or imidazolium)-labeled 1,3,4-oxadiazole thioethers as promising antibacterial agents against plant bacterial diseases. Journal of Agricultural and Food Chemistry, 2019, 67( 13): 3535– 3545 https://doi.org/10.1021/acs.jafc.8b06242
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D Zhang, Y Zhou, D Zhao, J Zhu, Z Yang, M Zhu. Complete genome sequence and pathogenic genes analysis of Pectobacterium atroseptica JG10-08. Genes & Genomics, 2017, 39( 9): 945– 955 https://doi.org/10.1007/s13258-017-0559-y
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S Wu, J Shi, J Chen, D Hu, L Zang, B Song. Synthesis, antibacterial activity, and mechanisms of novel 6-sulfonyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives. Journal of Agricultural and Food Chemistry, 2021, 69( 16): 4645– 4654 https://doi.org/10.1021/acs.jafc.1c01204
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X J Fan, D Kong, S He, J Z Chen, Y Jiang, Z Q Ma, J T Feng, H Yan. Phenanthrene derivatives from Asarum heterotropoides showed excellent antibacterial activity against phytopathogenic bacteria. Journal of Agricultural and Food Chemistry, 2021, 69( 48): 14520– 14529 https://doi.org/10.1021/acs.jafc.1c04385
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I Montenegro, M Valenzuela, N Zamorano, R Santander, C Baez, A Madrid. Activity of Adesmia boronioides resinous exudate against phytopathogenic bacteria. Natural Product Research, 2021, 35( 12): 2072– 2075 https://doi.org/10.1080/14786419.2019.1648465
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L B Lin, Y Q Gao, R Han, J Xiao, Y M Wang, Q Zhang, Y J Zhai, W B Han, W L Li, J M Gao. Alkylated salicylaldehydes and prenylated indole alkaloids from the endolichenic fungus Aspergillus chevalieri and their bioactivities. Journal of Agricultural and Food Chemistry, 2021, 69( 23): 6524– 6534 https://doi.org/10.1021/acs.jafc.1c01148
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L B Lin, J Xiao, Q Zhang, R Han, B Xu, S X Yang, W B Han, J J Tang, J M Gao. Eremophilane sesquiterpenoids with antibacterial and anti-inflammatory activities from the endophytic fungus Septoria rudbeckiae. Journal of Agricultural and Food Chemistry, 2021, 69( 40): 11878– 11889 https://doi.org/10.1021/acs.jafc.1c04131
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M Xiang, X Zhou, T R Luo, P Y Wang, L W Liu, Z Li, Z B Wu, S Yang. Design, synthesis, antibacterial evaluation, and induced apoptotic behaviors of epimeric and chiral 18β-glycyrrhetinic acid ester derivatives with an isopropanolamine bridge against phytopathogens. Journal of Agricultural and Food Chemistry, 2019, 67( 48): 13212– 13220 https://doi.org/10.1021/acs.jafc.9b06147
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M Xiang, Y L Song, J Ji, X Zhou, L W Liu, P Y Wang, Z B Wu, Z Li, S Yang. Synthesis of novel 18β-glycyrrhetinic piperazine amides displaying significant in vitro and in vivo antibacterial activities against intractable plant bacterial diseases. Pest Management Science, 2020, 76( 9): 2959– 2971 https://doi.org/10.1002/ps.5841
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S Jiang, S Su, M Chen, F Peng, Q Zhou, T Liu, L Liu, W Xue. Antibacterial activities of novel dithiocarbamate-containing 4H-chromen-4-one derivatives. Journal of Agricultural and Food Chemistry, 2020, 68( 20): 5641– 5647 https://doi.org/10.1021/acs.jafc.0c01652
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S Jiang, X Tang, M Chen, J He, S Su, L Liu, M He, W Xue. Design, synthesis and antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. citri and Ralstonia solanacearum of novel myricetin derivatives containing sulfonamide moiety. Pest Management Science, 2020, 76( 3): 853– 860 https://doi.org/10.1002/ps.5587
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Y J Chen, H Liu, S Y Zhang, H Li, K Y Ma, Y Q Liu, X D Yin, R Zhou, Y F Yan, R X Wang, Y H He, Q R Chu, C Tang. Design, synthesis, and antifungal evaluation of cryptolepine derivatives against phytopathogenic fungi. Journal of Agricultural and Food Chemistry, 2021, 69( 4): 1259– 1271 https://doi.org/10.1021/acs.jafc.0c06480
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J Lavrado, G G Cabal, M Prudencio, M M Mota, J Gut, P J Rosenthal, C Diaz, R C Guedes, D J dos Santos, E Bichenkova, K T Douglas, R Moreira, A Paulo. Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies. Journal of Medicinal Chemistry, 2011, 54( 3): 734– 750 https://doi.org/10.1021/jm101383f
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M Figueiras, L Coelho, K J Wicht, S A Santos, J Lavrado, J Gut, P J Rosenthal, F Nogueira, T J Egan, R Moreira, A Paulo. N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity. Bioorganic & Medicinal Chemistry, 2015, 23( 7): 1530– 1539 https://doi.org/10.1016/j.bmc.2015.02.007
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R Mudududdla, D Mohanakrishnan, S S Bharate, R A Vishwakarma, D Sahal, S B Bharate. Orally effective aminoalkyl 10H-indolo[3,2-b]quinoline-11-carboxamide kills the malaria parasite by inhibiting host hemoglobin uptake. ChemMedChem, 2018, 13( 23): 2581– 2598 https://doi.org/10.1002/cmdc.201800579
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J M Yuan, K Wei, G H Zhang, N Y Chen, X W Wei, C X Pan, D L Mo, G F Su. Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: design, synthesis and DNA targeting-induced apoptosis. European Journal of Medicinal Chemistry, 2019, 169 : 144– 158 https://doi.org/10.1016/j.ejmech.2019.02.072
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Q P Qin, Z Z Wei, Z F Wang, X L Huang, M X Tan, H H Zou, H Liang. Imaging and therapeutic applications of Zn(II)-cryptolepine-curcumin molecular probes in cell apoptosis detection and photodynamic therapy. Chemical Communications (Cambridge), 2020, 56( 28): 3999– 4002 https://doi.org/10.1039/D0CC00524J
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O A Olajide, A M Ajayi, C W Wright. Anti-inflammatory properties of cryptolepine. Phytotherapy Research, 2009, 23( 10): 1421– 1425 https://doi.org/10.1002/ptr.2794
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O A Olajide, H S Bhatia, A C de Oliveira, C W Wright, B L Fiebich. Anti-neuroinflammatory properties of synthetic cryptolepine in human neuroblastoma cells: possible involvement of NF-kappaB and p38 MAPK inhibition. European Journal of Medicinal Chemistry, 2013, 63 : 333– 339 https://doi.org/10.1016/j.ejmech.2013.02.004
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H Rasouli, R Yarani, F Pociot, J Popovic-Djordjevic. Anti-diabetic potential of plant alkaloids: revisiting current findings and future perspectives. Pharmacological Research, 2020, 155 : 104723– 104737 https://doi.org/10.1016/j.phrs.2020.104723
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S Y Ablordeppey, P C Fan, S M Li, A M Clark, C D Hufford. Substituted indoloquinolines as new antifungal agents. Bioorganic & Medicinal Chemistry, 2002, 10( 5): 1337– 1346 https://doi.org/10.1016/S0968-0896(01)00401-1
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C A Boateng, X Y Zhu, M R Jacob, S I Khan, L A Walker, S Y Ablordeppey. Optimization of 3-(phenylthio)quinolinium compounds against opportunistic fungal pathogens. European Journal of Medicinal Chemistry, 2011, 46( 5): 1789– 1797 https://doi.org/10.1016/j.ejmech.2011.02.034
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M Zhao, T Kamada, A Takeuchi, H Nishioka, T Kuroda, Y Takeuchi. Structure-activity relationship of indoloquinoline analogs anti-MRSA. Bioorganic & Medicinal Chemistry Letters, 2015, 25( 23): 5551– 5554 https://doi.org/10.1016/j.bmcl.2015.10.058
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N Sun, R L Du, Y Y Zheng, B H Huang, Q Guo, R F Zhang, K Y Wong, Y J Lu. Antibacterial activity of N-methylbenzofuro[3,2-b]quinoline and N-methylbenzoindolo[3,2-b]-quinoline derivatives and study of their mode of action. European Journal of Medicinal Chemistry, 2017, 135 : 1– 11 https://doi.org/10.1016/j.ejmech.2017.04.018
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S Gibbons, F Fallah, C W Wright. Cryptolepine hydrochloride: a potent antimycobacterial alkaloid derived from Cryptolepis sanguinolenta. Phytotherapy Research, 2003, 17( 4): 434– 436 https://doi.org/10.1002/ptr.1284
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N Tuyiringire, S Deyno, A Weisheit, C U Tolo, D Tusubira, J P Munyampundu, P E Ogwang, C M Muvunyi, Y V Heyden. Three promising antimycobacterial medicinal plants reviewed as potential sources of drug hit candidates against multidrug-resistant tuberculosis. Tuberculosis (Edinburgh, Scotland), 2020, 124 : 101987– 101994 https://doi.org/10.1016/j.tube.2020.101987
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Q R Chu, Y H He, C Tang, Z J Zhang, X F Luo, B Q Zhang, Y Zhou, T L Wu, S S Du, C J Yang, Y Q Liu. Design, synthesis, and antimicrobial activity of quindoline derivatives inspired by the cryptolepine alkaloid. Journal of Agricultural and Food Chemistry, 2022, 70( 9): 2851– 2863 https://doi.org/10.1021/acs.jafc.1c07536
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I Wiegand, K Hilpert, R E Hancock. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nature Protocols, 2008, 3( 2): 163– 175 https://doi.org/10.1038/nprot.2007.521
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T Fan, W Guo, T Shao, W Zhou, P Hu, M Liu, Y Chen, Z Yi. Design, synthesis and evaluation of phenylthiazole and phenylthiophene pyrimidindiamine derivatives targeting the bacterial membrane. European Journal of Medicinal Chemistry, 2020, 190 : 112141– 112153 https://doi.org/10.1016/j.ejmech.2020.112141
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J Chen, Y Luo, C Wei, S Wu, R Wu, S Wang, D Hu, B Song. Novel sulfone derivatives containing a 1,3,4-oxadiazole moiety: design and synthesis based on the 3D-QSAR model as potential antibacterial agent. Pest Management Science, 2020, 76( 9): 3188– 3198 https://doi.org/10.1002/ps.5873
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C F Yi, J X Chen, C Q Wei, S K Wu, S B Wang, D Y Hu, B A Song. α-Haloacetophenone and analogues as potential antibacterial agents and nematicides. Bioorganic & Medicinal Chemistry Letters, 2020, 30( 2): 126814– 126818 https://doi.org/10.1016/j.bmcl.2019.126814
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S Kang, F Kong, X Shi, H Han, M Li, B Guan, M Yang, X Cao, D Tao, Y Zheng, X Yue. Antibacterial activity and mechanism of lactobionic acid against Pseudomonas fluorescens and Methicillin-resistant Staphylococcus aureus and its application on whole milk. Food Control, 2020, 108 : 106876– 106885 https://doi.org/10.1016/j.foodcont.2019.106876
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L Zhao, F Duan, M Gong, X Tian, Y Guo, L Jia, S Deng. (+)-Terpinen-4-ol inhibits Bacillus cereus biofilm formation by upregulating the interspecies quorum sensing signals diketopiperazines and diffusing signaling factors. Journal of Agricultural and Food Chemistry, 2021, 69( 11): 3496– 3510 https://doi.org/10.1021/acs.jafc.0c07826
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L Qi, H Li, C Zhang, B Liang, J Li, L Wang, X Du, X Liu, S Qiu, H Song. Relationship between antibiotic resistance, biofilm formation, and biofilm-specific resistance in Acinetobacter baumannii. Frontiers in Microbiology, 2016, 7 : 483– 492 https://doi.org/10.3389/fmicb.2016.00483
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J W Zhou, L Y Ruan, H J Chen, H Z Luo, H Jiang, J S Wang, A Q Jia. Inhibition of quorum sensing and virulence in Serratia marcescens by hordenine. Journal of Agricultural and Food Chemistry, 2019, 67( 3): 784– 795 https://doi.org/10.1021/acs.jafc.8b05922
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T K Beuria, M K Santra, D Panda. Sanguinarine blocks cytokinesis in bacteria by inhibiting FtsZ assembly and bundling. Biochemistry, 2005, 44( 50): 16584– 16593 https://doi.org/10.1021/bi050767+
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