Skip to main content

Advertisement

SpringerLink
Log in

Design and synthesis of novel 2,2-dimethylchromene derivatives as potential antifungal agents

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

In order to find novel environment-friendly and effective antifungal agents, four series of 2,2-dimethyl-2H-chromene derivatives were designed, synthesized and characterized by spectroscopic analysis. The antifungal activities of all the target compounds against nine phytopathogenic fungi were evaluated in vitro. Preliminary results indicated that most of the target compounds exhibited obvious antifungal activity at the concentration of 50 μg/mL. Among them, compound 4j displayed more promising antifungal potency against Fusarium solani, Pyricularia oryzae, Alternaria brassicae, Valsa mali and Alternaria alternata strains than the two commercially available fungicides chlorothalonil and hymexazol, with the corresponding EC50 values of 6.3, 7.7, 7.1, 7.5, 4.0 μg/mL, respectively. Moreover, the cell experiments results suggested that the target compounds had low cytotoxicity to the PC12 cell. This research will provide theoretical basis for the future application of 2,2-dimethyl-2H-chromenes as botanical fungicides in agriculture.

Graphical Abstract

Four series of novel, potent and low-toxicity 2,2-dimethyl-2H-chromene derivatives were designed and synthesized as agricultural antifungal agents. The in vitro antifungal experiments showed that compound 4j exhibited higher antifungal efficacy against five strains than the two commercially-available fungicides chlorothalonil and hymexazol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Scheme 3
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ons L, Bylemans D, Thevissen K, Cammue BPA (2020) Combining biocontrol agents with chemical fungicides for integrated plant fungal disease control. Microorganisms 8(12):1930. https://doi.org/10.3390/microorganisms8121930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brauer VS, Rezende CP, Pessoni AM, Paula RG, Rangappa SK, Nayaka SC, Gupta VK, Almeida F (2019) Antifungal agents in agriculture: friends and foes of public health. Biomolecules 9:521. https://doi.org/10.3390/biom9100521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sparks TC, Bryant RJ (2021) Impact of natural products on discovery of, and innovation in, crop protection compounds. Pest Manag Sci. https://doi.org/10.1002/ps.6653

    Article  PubMed  PubMed Central  Google Scholar 

  4. Agarwal SK, Verma S, Singh SS, Tripathi AK, Khan ZK, Kumar S (2000) Antifeedant and antifungal activity of chromene compounds isolated from Blepharispermum subsessile. J Ethnopharmacol 71(1–2):231–234. https://doi.org/10.1016/S0378-8741(00)00158-6

    Article  CAS  PubMed  Google Scholar 

  5. Meepagala KM, Schrader KK, Burandt CL, Wedge DE, Duke SO (2010) New class of algicidal compounds and fungicidal activities derived from a chromene amide of Amyris texana. J Agr Food Chem 58(17):9476–9482. https://doi.org/10.1021/jf101626g

    Article  CAS  Google Scholar 

  6. Saga Kitamura RO, Romoff P, Young MCM, Kato MJ, Lago JHG (2006) Chromenes from Peperomia serpens (Sw.) Loudon (Piperaceae). Phytochemistry 67(21):2398–2402. https://doi.org/10.1016/j.phytochem.2006.08.007

    Article  CAS  PubMed  Google Scholar 

  7. Malquichagua Salazar KJ, Delgado Paredes GE, Lluncor LR, Young MCM, Kato MJ (2005) Chromenes of polyketide origin from Peperomia villipetiola. Phytochemistry 66(5):573–579. https://doi.org/10.1016/j.phytochem.2005.01.003

    Article  CAS  PubMed  Google Scholar 

  8. Yadav N, Ganie SA, Singh B, Chhillar AK, Yadav SS (2019) Phytochemical constituents and ethnopharmacological properties of Ageratum conyzoides L. Phytother Res 33(9):2163–2178. https://doi.org/10.1002/ptr.6405

    Article  PubMed  Google Scholar 

  9. Zheng GW, Luo SH, Li SF, Hua J, Li WQ, Li SH (2018) Specialized metabolites from Ageratina adenophora and their inhibitory activities against pathogenic fungi. Phytochemistry 148:57–62. https://doi.org/10.1016/j.phytochem.2018.01.013

    Article  CAS  PubMed  Google Scholar 

  10. Pratap R, Ram VJ (2014) Natural and synthetic chromenes, fused chromenes, and versatility of dihydrobenzo[h]chromenes in organic synthesis. Chem Rev 114(20):10476–10526. https://doi.org/10.1021/cr500075s

    Article  CAS  PubMed  Google Scholar 

  11. Simmler C, Pauli GF, Chen SN (2013) Phytochemistry and biological properties of glabridin. Fitoterapia 90:160–184. https://doi.org/10.1016/j.fitote.2013.07.003

    Article  CAS  PubMed  Google Scholar 

  12. Lee JW, Choe SS, Jang H, Kim J, Jeong HW, Jeong KH, Tadi S, Park MG, Kwak TH, Kim JM, Hyun DH, Bum Kim JB (2012) AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. J Lipid Res 53:1277–1286. https://doi.org/10.1194/jlr.m022897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pratt GE, Jennings RC, Hamnett AF, Brooks GT (1980) Lethal metabolism of precocene-I to a reactive epoxide by locust Corpora allata. Nature 284:320–323. https://doi.org/10.1038/284320a0

    Article  CAS  Google Scholar 

  14. Mao LX, Henderson G, Dong SL (2010) Studies of precocene I, precocene II and biogenic amines on formosan subterranean Termite (Isoptera: Rhinotermitidae) presoldier/soldier formation. J Entomol Sci 45(1):27–34. https://doi.org/10.18474/0749-8004-45.1.27

    Article  CAS  Google Scholar 

  15. Samnesh ET, Tayebeh R, Hassan E, Vahid N (2010) Composition of essential oils in subterranean organs of three species of Valeriana L. Nat Prod Res 24:1834–1842. https://doi.org/10.1080/14786419.2010.482051

    Article  CAS  Google Scholar 

  16. Parra JE, Delgado WA, Cuca LE (2011) Cumanensic acid, a new chromene isolated from Piper cf. cumanense Kunth. (Piperaceae). Phytochem Lett 4(3):280–282. https://doi.org/10.1016/j.phytol.2011.04.015

    Article  CAS  Google Scholar 

  17. Abrunhosa L, Costa M, Areias F, Venâncio A, Proença F (2007) Antifungal activity of a novel chromene dimer. J Ind Microbiol Biot 34(12):787–792. https://doi.org/10.1007/s10295-007-0255-z

    Article  CAS  Google Scholar 

  18. Xu H, Fan LL (2011) Synthesis and antifungal activities of novel 5,6-dihydroindolo-[1,2-a]quinoxaline derivatives. Eur J Med Chem 46(5):1919–1925. https://doi.org/10.1016/j.ejmech.2011.02.035

    Article  CAS  PubMed  Google Scholar 

  19. Xu H, Fan LL (2011) Antifungal agents. Part 4: synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro. Eur J Med Chem 46(1):364–369. https://doi.org/10.1016/j.ejmech.2010.10.022

    Article  CAS  PubMed  Google Scholar 

  20. Fan LL, Luo BL, Luo ZF, Zhang L, Fan JD, Xue W, Tang L, Li Y (2019) Synthesis and antifungal activities of 3-substituted phthalide derivatives. Z Naturforsch B 74(11–12):811–818. https://doi.org/10.1515/znb-2019-0110

    Article  CAS  Google Scholar 

  21. Li Y, Luo ZF, Luo BL, Lan Q, Fan JD, Xue W, Miao J, Li Y, Tang L, Fan LL (2020) Design, synthesis and antifungal activities of 6-substituted 3-butylphthalide derivatives against phytopathogenic fungi. Chem Biodivers 17:e2000435. https://doi.org/10.1002/cbdv.202000435

    Article  CAS  PubMed  Google Scholar 

  22. Fan LL, Luo ZF, Li Y, Liu XY, Fan JD, Xue W, Tang L, Li Y (2020) Synthesis and antifungal activity of imidazo[1,2-b]pyridazine derivatives against phytopathogenic fungi. Bioorg Med Chem Lett 30:127139. https://doi.org/10.1016/j.bmcl.2020.127139

    Article  CAS  PubMed  Google Scholar 

  23. Luo ZF, Deng Y, Luo BL, Li Y, Lan Q, Fan JD, Xue W, Tang L, Fan LL (2021) Design and synthesis of novel n-butyphthalide derivatives as promising botanical fungicides. Z Naturforsch C 76(3–4):117–127. https://doi.org/10.1515/znc-2020-0192

    Article  CAS  PubMed  Google Scholar 

  24. Fan LL, Luo ZF, Yang CF, Tang L, Li Y (2021) Design and synthesis of small molecular 2-aminobenzoxazoles as potential antifungal agents against phytopathogenic fungi. Mol Divers. https://doi.org/10.1007/s11030-021-10213-7

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang CP, Xie LJ, Ma YQ, Cai XW, Yue GZ, Qin GG, Zhang M, Gong GS, Chang XL, Qiu XY, Luo LY, Chen HB (2021) Study on the fungicidal mechanism of glabridin against Fusarium graminearum. Pestici Biochem Phys 179:104963. https://doi.org/10.1016/j.pestbp.2021.104963

    Article  CAS  Google Scholar 

  26. López-López E, Bajorath J, Medina-Franco JL (2021) Informatics for chemistry, biology, and biomedical Sciences. J Chem Inf Model 61(1):26–35. https://doi.org/10.1021/acs.jcim.0c01301

    Article  CAS  PubMed  Google Scholar 

  27. Ishikawa T, Mizutani A, Miwa C, Oku Y, Komano N, Takami A, Watanabe T (1997) Cesium fluoride-mediated claisen rearrangements of phenyl propargyl ethers: substituent effects of an ortho-alkoxy group on the benzene ring or modified propargyl residues. Heterocycles 45(11):2261–2272. https://doi.org/10.3987/com-97-7946

    Article  CAS  Google Scholar 

  28. Soussi MA, Audisio D, Messaoudi S, Provot O, Brion JD, Alami M (2011) Palladium-catalyzed coupling of 3-halo-substituted coumarins, chromenes, and quinolones with various nitrogen-containing nucleophiles. Eur J Org Chem 26:5077–5088. https://doi.org/10.1002/ejoc.201100480

    Article  CAS  Google Scholar 

  29. Ji WH, Gao QS, Lin YL, Gao HM, Wang X, Geng YL (2014) Total synthesis of (±)-glabridin. Synth Commun 44(4):540–546. https://doi.org/10.1080/00397911.2013.821616

    Article  CAS  Google Scholar 

  30. Salvatore MM, Andolfi A (2021) Phytopathogenic fungi and toxicity. Toxins 13(10):689. https://doi.org/10.3390/toxins13100689

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wu W, Zhou J, Pan XX, Pan Q, Shi L, Zang LQ (2009) Experimental study on primary rat cortical neurons and PC12 cells used for the evaluation of acute cytotoxicity. J Clin Res 26(3):369–373. https://doi.org/10.3969/j.issn.1671-7171.2009.03.001

    Article  Google Scholar 

  32. Fournier L, Aujard I, Saux TL, Maurin S, Beaupierre S, Baudin JB, Jullien L (2013) Coumarinylmethyl caging groups with redshifted absorption. Chem Eur J 19(51):17494–17507. https://doi.org/10.1002/chem.201302630

    Article  CAS  PubMed  Google Scholar 

  33. Chen L, Hu TS, Yao ZJ (2008) Development of new pyrrolocoumarin derivatives with satisfactory fluorescent properties and notably large stokes shifts. Eur J Org Chem 36:6175–6182. https://doi.org/10.1002/ejoc.200800883

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by The National Natural Science Foundation of China (No.32060627). Guizhou Provincial Natural Science Foundation (No. [2020]1Y111), The State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering/Key Laboratory of Ministry of Education, Guizhou University (No. 2021GDP0101, QJHKYZ[2022]362 and QJHKYZ[2020]250), The Project of Postgraduate Scientific Research Fund of Guizhou (No. YJSKYJJ [2021] 152).

Author information

Authors and Affiliations

  1. School of Basic Medical Sciences, State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550004, People’s Republic of China

    Yong Li, Bilan Luo, Zhongfu Luo, Taigui Ma, Lingling Fan, Wenjing Liu, Judi Fan, Bing Guo & Lei Tang

  2. Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, People’s Republic of China

    Wei Xue

Authors
  1. Yong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bilan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhongfu Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taigui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lingling Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenjing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Judi Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bing Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lei Tang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15601 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Luo, B., Luo, Z. et al. Design and synthesis of novel 2,2-dimethylchromene derivatives as potential antifungal agents. Mol Divers 27, 589–601 (2023). https://doi.org/10.1007/s11030-022-10421-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-022-10421-9

Keywords

Search

Navigation