Discovery of cryptolepine derivatives as novel promising agents against phytopathogenic bacteria

Abstract

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.

Key words： cryptolepine derivatives; phytopathogenic bacteria; antibacterial activity; mechanism of action

Acknowledgements

This work was supported financially by the National Natural Science Foundation of China (Grant Nos. 22177043 and 21877056) and the Natural Science Foundation of Gansu Province (Grant No. 20JR5RA311); the support was also supplied by the Key Program for International S&T Cooperation Projects of Gansu Province of China (Grant No. 18YF1WA115).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://dx.doi.org/10.1007/s11705-022-2196-5 and is accessible for authorized users.

References

1 LiP, HuD, XieD, ChenJ, JinL, SongB. 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

2 WangP Y, WangM W, ZengD, XiangM, RaoJ R, LiuQ Q, LiuL W, WuZ B, LiZ, SongB A, YangS. 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

3 ZhangD, ZhouY, ZhaoD, ZhuJ, YangZ, ZhuM. Complete genome sequence and pathogenic genes analysis of Pectobacterium atroseptica JG10-08. Genes & Genomics, 2017, 39( 9): 945– 955

4 WuS, ShiJ, ChenJ, HuD, ZangL, SongB. 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

5 FanX J, KongD, HeS, ChenJ Z, JiangY, MaZ Q, FengJ T, YanH. Phenanthrene derivatives from Asarum heterotropoides showed excellent antibacterial activity against phytopathogenic bacteria. Journal of Agricultural and Food Chemistry, 2021, 69( 48): 14520– 14529

6 MontenegroI, ValenzuelaM, ZamoranoN, SantanderR, BaezC, MadridA. Activity of Adesmia boronioides resinous exudate against phytopathogenic bacteria. Natural Product Research, 2021, 35( 12): 2072– 2075

7 LinL B, GaoY Q, HanR, XiaoJ, WangY M, ZhangQ, ZhaiY J, HanW B, LiW L, GaoJ M. 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

8 LinL B, XiaoJ, ZhangQ, HanR, XuB, YangS X, HanW B, TangJ J, GaoJ M. 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

9 XiangM, ZhouX, LuoT R, WangP Y, LiuL W, LiZ, WuZ B, YangS. 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

10 XiangM, SongY L, JiJ, ZhouX, LiuL W, WangP Y, WuZ B, LiZ, YangS. 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

11 JiangS, SuS, ChenM, PengF, ZhouQ, LiuT, LiuL, XueW. Antibacterial activities of novel dithiocarbamate-containing 4H-chromen-4-one derivatives. Journal of Agricultural and Food Chemistry, 2020, 68( 20): 5641– 5647

12 JiangS, TangX, ChenM, HeJ, SuS, LiuL, HeM, XueW. 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

13 ChenY J, LiuH, ZhangS Y, LiH, MaK Y, LiuY Q, YinX D, ZhouR, YanY F, WangR X, HeY H, ChuQ R, TangC. Design, synthesis, and antifungal evaluation of cryptolepine derivatives against phytopathogenic fungi. Journal of Agricultural and Food Chemistry, 2021, 69( 4): 1259– 1271

14 LavradoJ, CabalG G, PrudencioM, MotaM M, GutJ, RosenthalP J, DiazC, GuedesR C, dos SantosD J, BichenkovaE, DouglasK T, MoreiraR, PauloA. Incorporation of basic side chains into cryptolepine scaffold: structure-antimalarial activity relationships and mechanistic studies. Journal of Medicinal Chemistry, 2011, 54( 3): 734– 750

15 FigueirasM, CoelhoL, WichtK J, SantosS A, LavradoJ, GutJ, RosenthalP J, NogueiraF, EganT J, MoreiraR, PauloA. 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

16 MudududdlaR, MohanakrishnanD, BharateS S, VishwakarmaR A, SahalD, BharateS B. 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

17 YuanJ M, WeiK, ZhangG H, ChenN Y, WeiX W, PanC X, MoD L, SuG F. 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

18 QinQ P, WeiZ Z, WangZ F, HuangX L, TanM X, ZouH H, LiangH. 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

19 OlajideO A, AjayiA M, WrightC W. Anti-inflammatory properties of cryptolepine. Phytotherapy Research, 2009, 23( 10): 1421– 1425

20 OlajideO A, BhatiaH S, de OliveiraA C, WrightC W, FiebichB L. 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

21 RasouliH, YaraniR, PociotF, Popovic-DjordjevicJ. Anti-diabetic potential of plant alkaloids: revisiting current findings and future perspectives. Pharmacological Research, 2020, 155 : 104723– 104737

22 AblordeppeyS Y, FanP C, LiS M, ClarkA M, HuffordC D. Substituted indoloquinolines as new antifungal agents. Bioorganic & Medicinal Chemistry, 2002, 10( 5): 1337– 1346

23 BoatengC A, ZhuX Y, JacobM R, KhanS I, WalkerL A, AblordeppeyS Y. Optimization of 3-(phenylthio)quinolinium compounds against opportunistic fungal pathogens. European Journal of Medicinal Chemistry, 2011, 46( 5): 1789– 1797

24 ZhaoM, KamadaT, TakeuchiA, NishiokaH, KurodaT, TakeuchiY. Structure-activity relationship of indoloquinoline analogs anti-MRSA. Bioorganic & Medicinal Chemistry Letters, 2015, 25( 23): 5551– 5554

25 SunN, DuR L, ZhengY Y, HuangB H, GuoQ, ZhangR F, WongK Y, LuY J. 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

26 GibbonsS, FallahF, WrightC W. Cryptolepine hydrochloride: a potent antimycobacterial alkaloid derived from Cryptolepis sanguinolenta. Phytotherapy Research, 2003, 17( 4): 434– 436

27 TuyiringireN, DeynoS, WeisheitA, ToloC U, TusubiraD, MunyampunduJ P, OgwangP E, MuvunyiC M, HeydenY V. Three promising antimycobacterial medicinal plants reviewed as potential sources of drug hit candidates against multidrug-resistant tuberculosis. Tuberculosis (Edinburgh, Scotland), 2020, 124 : 101987– 101994

28 ChuQ R, HeY H, TangC, ZhangZ J, LuoX F, ZhangB Q, ZhouY, WuT L, DuS S, YangC J, LiuY Q. Design, synthesis, and antimicrobial activity of quindoline derivatives inspired by the cryptolepine alkaloid. Journal of Agricultural and Food Chemistry, 2022, 70( 9): 2851– 2863

29 WiegandI, HilpertK, HancockR E. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nature Protocols, 2008, 3( 2): 163– 175

30 FanT, GuoW, ShaoT, ZhouW, HuP, LiuM, ChenY, YiZ. Design, synthesis and evaluation of phenylthiazole and phenylthiophene pyrimidindiamine derivatives targeting the bacterial membrane. European Journal of Medicinal Chemistry, 2020, 190 : 112141– 112153

31 ChenJ, LuoY, WeiC, WuS, WuR, WangS, HuD, SongB. 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

32 YiC F, ChenJ X, WeiC Q, WuS K, WangS B, HuD Y, SongB A. α-Haloacetophenone and analogues as potential antibacterial agents and nematicides. Bioorganic & Medicinal Chemistry Letters, 2020, 30( 2): 126814– 126818

33 KangS, KongF, ShiX, HanH, LiM, GuanB, YangM, CaoX, TaoD, ZhengY, YueX. 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

34 ZhaoL, DuanF, GongM, TianX, GuoY, JiaL, DengS. (+)-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

35 QiL, LiH, ZhangC, LiangB, LiJ, WangL, DuX, LiuX, QiuS, SongH. Relationship between antibiotic resistance, biofilm formation, and biofilm-specific resistance in Acinetobacter baumannii. Frontiers in Microbiology, 2016, 7 : 483– 492

36 ZhouJ W, RuanL Y, ChenH J, LuoH Z, JiangH, WangJ S, JiaA Q. Inhibition of quorum sensing and virulence in Serratia marcescens by hordenine. Journal of Agricultural and Food Chemistry, 2019, 67( 3): 784– 795

37 BeuriaT K, SantraM K, PandaD. Sanguinarine blocks cytokinesis in bacteria by inhibiting FtsZ assembly and bundling. Biochemistry, 2005, 44( 50): 16584– 16593

38 DomadiaP N, BhuniaA, SivaramanJ, SwarupS, DasguptaD. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry, 2008, 47( 10): 3225– 3234