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Novel pyran derivatives as potential succinate dehydrogenase inhibitors: design, synthesis, crystal structure, biological activity, and molecular modeling

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Abstract

Twenty-six novel pyran derivatives (1a−m, 2a−m) were designed, synthesized, and characterized by IR, 1H NMR, 13C NMR, and HRMS. The crystal structures of compound 2f was characterized by single crystal X-ray diffraction and crystallized in the monoclinic system with space group P21/c. The in vitro antifungal activities of these synthesized compounds were evaluated against five plant pathogenic fungi namely Gibberella zeae, Helminthosporium maydis, Rhizoctonia solani, Penicillium digitatum, and Sclerotinia sclerotiorum and most of the synthesized compounds displayed good to excellent antifungal activities at 20 µg/mL. Of these, the inhibitory rates and the median effect concentrations (EC50) of compound 2e against R. Solani, compounds 1b, 1e, 2a, 2b, and 2c against S. sclerotiorum, and compounds 1a and 2i against H. maydis were better than fluopyram against the relative fungi. Besides, the half inhibitory concentrations (IC50) of compounds 1b, 1e, 2a, 2b, and 2c against succinate dehydrogenase (SDH) and their scores in molecular docking were both lower than that of fluopyram, indicating that these synthesized compounds possessed stronger antifungal activities and affinities than fluopyram. Therefore, we concluded that compounds 1b, 1e, 2a, 2b, and 2c might serve as potential succinate dehydrogenase inhibitors (SDHIs), which was been reported for the first time.

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References

  1. Jin H, Zhou J, Pu T, Zhang A, Gao X, Tao K, et al. Synthesis of novel fenfuram-diarylether hybrids as potent succinate dehydrogenase inhibitors. Bioorg Chem. 2017;73:76–82.

    Article  CAS  PubMed  Google Scholar 

  2. Xiong L, Li H, Jiang LN, Ge JM, Yang WC, Zhu XL, et al. Structure-based discovery of potential fungicides as succinate ubiquinone oxidoreductase inhibitors. J Agric Food Chem. 2017;65:1021–9.

    Article  CAS  PubMed  Google Scholar 

  3. Yao TT, Fang SW, Li ZS, Xiao DX, Cheng JL, Ying HZ, et al. Discovery of novel succinate dehydrogenase inhibitors by the integration of in silico library design and pharmacophore mapping. J Agric Food Chem. 2017;65:3204–11.

    Article  CAS  PubMed  Google Scholar 

  4. Yao TT, Xiao DX, Li ZS, Cheng JL, Fang SW, Du YJ, et al. Design, synthesis, and fungicidal evaluation of novel pyrazole-furan and pyrazole-pyrrole carboxamide as succinate dehydrogenase inhibitors. J Agric Food Chem. 2017;65:5397–403.

    Article  CAS  PubMed  Google Scholar 

  5. Lu T, Yan Y, Zhang T, Zhang G, Xiao T, Cheng W, et al. Design, synthesis, biological evaluation, and molecular modeling of novel 4h-chromene analogs as potential succinate dehydrogenase inhibitors. J Agric Food Chem. 2021;69:10709–21.

    Article  CAS  PubMed  Google Scholar 

  6. Cheng W, Yan Y, Xiao T, Zhang G, Zhang T, Lu T, et al. Design, synthesis and inhibitory activity of novel 2, 3-dihydroquinolin-4(1H)-one derivatives as potential succinate dehydrogenase inhibitors. Eur J Med Chem. 2021;214:113246.

    Article  CAS  PubMed  Google Scholar 

  7. Wang XS, Tang XR, Peng MJ, Mai YZ. Design, synthesis, and antifungal activity evaluation of novel 2-cyano-5-oxopentanoic acid derivatives as potential succinate dehydrogenase inhibitors. Med Chem Res. 2022;31:94–107.

    Article  CAS  Google Scholar 

  8. Chen Y, Zhang AF, Wang WX, Zhang Y, Gao TC. Baseline sensitivity and efficacy of thifluzamide in Rhizoctonia solani. Ann Appl Biol. 2012;161:247–54.

    Article  CAS  Google Scholar 

  9. Yanase Y, Kishi J, Inami S, Katsuta H, Yoshikawa Y. Biological activity and disease controlling efficacy of penthiopyrad. J Pestic Sci. 2013;38:188–93.

    Article  CAS  Google Scholar 

  10. Veloukas T, Karaoglanidis GS. Biological activity of the succinate dehydrogenase inhibitor fluopyram against Botrytis cinerea and fungal baseline sensitivity. Pest Manag Sci. 2012;68:858–64.

    Article  CAS  PubMed  Google Scholar 

  11. Hou YP, Mao XW, Lin SP, Song XS, Duan YB, Wang JX, et al. Activity of a novel succinate dehydrogenase inhibitor fungicide pyraziflumid against Sclerotinia sclerotiorum. Pestic Biochem Physiol. 2018;145:22–8.

    Article  CAS  PubMed  Google Scholar 

  12. Huang XP, Song YF, Li BX, Mu W, Liu F. Baseline sensitivity of isopyrazam against Sclerotinia sclerotiorum and its efficacy for the control of Sclerotinia stem rot in vegetables. Crop Prot. 2019;122:42–8.

    Article  CAS  Google Scholar 

  13. Xiong L, Shen YQ, Jiang LN, Zhu XL, Yang WC, Huang W, et al. Succinate dehydrogenase: an ideal target for fungicide discovery. Discovery and synthesis of crop protection products. Washington, DC: American Chemical Society; 2015. p. 175–94. Chapter 13

    Google Scholar 

  14. Duso C, Van Leeuwen T, Pozzebon A. Improving the compatibility of pesticides and predatory mites: recent findings on physiological and ecological selectivity. Curr Opin Insect Sci. 2020;39:63–8.

    Article  PubMed  Google Scholar 

  15. Singh P, Singh J, Pant GJ, Rawat MSM. 2-Pyrazolines as biologically active and fluorescent agents, an overview. Anticancer Agents Med Chem. 2018;18:1366–85.

    Article  CAS  PubMed  Google Scholar 

  16. Zhu Q, Yang Y, Lao Z, Zhong Y, Zhang B, Cui X, et al. Synthesis, insecticidal activities and resistance in Aedes albopictus and cytotoxicity of novel dihaloacetylated heterocyclic pyrethroids. Pest Manag Sci. 2020;76:636–44.

    Article  CAS  PubMed  Google Scholar 

  17. Schilling W, Zhang Y, Riemer D, Das S. Visible-light-mediated dearomatisation of indoles and pyrroles to pharmaceuticals and pesticides. Chemistry. 2020;26:390–5.

    Article  CAS  PubMed  Google Scholar 

  18. Bhat AR, Athar F, Azam A. New derivatives of 3,5-substituted-1,4,2-dioxazoles: synthesis and activity against Entamoeba histolytica. Eur J Med Chem. 2009;44:926–36.

    Article  CAS  PubMed  Google Scholar 

  19. Ozdemir Z, Kandilci HB, Gümüşel B, Calis U, Bilgin AA. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med Chem. 2007;42:373–9.

    Article  PubMed  Google Scholar 

  20. Wang X, Tang X. Design, synthesis and evaluate in vitro antifungal activity of novel benzamide derivatives. J Chem Soc Pak. 2019;41:549–54.

    CAS  Google Scholar 

  21. Wang X, Gao S, Yang J, Gao Y, Wang L, Tang X. Synthesis and antifungal activity evaluation of new heterocycle containing amide derivatives. Nat Prod Res. 2016;30:682–8.

    Article  CAS  PubMed  Google Scholar 

  22. Botubol-Ares JM, Durán-Peña MJ, Hernández-Galán R, Collado IG, Harwood LM, Macías-Sánchez AJ. nor-Mevaldic acid surrogates as selective antifungal agent leads against Botrytis cinerea. Enantioselective preparation of 4-hydroxy-6-(1-phenylethoxy)tetrahydro-2H-pyran-2-one. Bioorg Med Chem. 2015;23:3379–87.

    Article  CAS  PubMed  Google Scholar 

  23. Shamroukh AH, Zaki ME, Morsy EM, Abdel-Motti FM, Abdel-Megeid FM. Synthesis, isomerization, and antimicrobial evaluation of some pyrazolopyranotriazolopyrimidine derivatives. Arch Pharm. 2007;340:345–51.

    Article  CAS  Google Scholar 

  24. Mansoor SS, Ghashang M. Synthesis of a novel series of 7-hydroxy-10-aryl-10H-indeno[1,2-b]chromen-11-ones, indeno[1,2-b]naphtho[1,2-e]pyran-12(13H)-one, and indeno[1,2-b]naphtho[3,2-e]pyran-5,11,13-trione catalyzed by reusable polyvinylpolypyrrolidone-supported triflic acid. Res Chem Intermediat. 2015;41:9085–100.

    Article  CAS  Google Scholar 

  25. Reddy TN, Ravinder M, Bikshapathi R, Sujitha P, Kumar CG, Rao VJ. Design, synthesis, and biological evaluation of 4-H pyran derivatives as antimicrobial and anticancer agents. Med Chem Res. 2017;26:2832–44.

    Article  CAS  Google Scholar 

  26. Saundane AR, Vijaykumar K, Vaijinath AV. Synthesis of novel 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents. Bioorg Med Chem Lett. 2013;23:1978–84.

    Article  CAS  PubMed  Google Scholar 

  27. de Andrade-Neto VF, Goulart MO, da Silva Filho JF, da Silva MJ, Pinto Mdo C, Pinto AV, et al. Antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. Bioorg Med Chem Lett. 2004;14:1145–9.

    Article  PubMed  Google Scholar 

  28. Burriss A, Edmunds AJ, Emery D, Hall RG, Jacob O, Schaetzer J. The importance of trifluoromethyl pyridines in crop protection. Pest Manag Sci. 2018;74:1228–38.

    Article  CAS  PubMed  Google Scholar 

  29. Kim DS, Chun SJ, Jeon JJ, Lee SW, Joe GH. Synthesis and fungicidal activity of ethaboxam against Oomycetes. Pest Manag Sci. 2004;60:1007–12.

    Article  CAS  PubMed  Google Scholar 

  30. Piqueras CM, Latorre BA, René T. Effectiveness of isofetamid, a new succinate dehydrogenase inhibitor fungicide, in the control of grapevine gray mold. Cien Inv Agr. 2014;41:365–74.

    Article  Google Scholar 

  31. Liu S, Fu L, Tan H, Jiang J, Che Z, Tian Y, et al. Resistance to Boscalid in Botrytis cinerea from greenhouse-grown tomato. Plant Dis. 2021;105:628–35.

    Article  PubMed  Google Scholar 

  32. Kahriman N, Serdarolu V, Peker K, Aydn A, Usta A. Synthesis and biological evaluation of new 2,4,6-trisubstituted pyrimidines and their N-alkyl derivatives. Bioorg Chem. 2018;83:580–94.

    Article  PubMed  Google Scholar 

  33. Kumar N, Chauhan A, Drabu S. Synthesis of cyanopyridine and pyrimidine analogues as new anti-inflammatory and antimicrobial agents. Biomed Pharmacother. 2011;65:375–80.

    Article  CAS  PubMed  Google Scholar 

  34. Jain S, Paliwal PK, Neelaiah Babu G, Bhatewara A. DABCO promoted one-pot synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]pyrimidine derivatives and their biological activities. J Saudi Chem Soc. 2014;18:535–40.

    Article  CAS  Google Scholar 

  35. Dolomanov OV, Bourhis LJ, Gildea RJ, Howard J, Puschmann H. OLEX2: a complete structure solution, refinement and analysis program. J Appl Crystallogr. 2010;42:339–41.

    Article  Google Scholar 

  36. Palatinus L, Chapuis G. SUPERFLIP—a computer program for the solution of crystal structures by charge flipping in arbitrary dimensions. J Appl Crystallogr. 2007;40:786–90.

    Article  CAS  Google Scholar 

  37. Palatinus L, Lee A. Symmetry determination following structure solution in P1. J Appl Crystallogr. 2008;41:975–84.

    Article  CAS  Google Scholar 

  38. Palatinus L, Prathapa SJ, Smaalen SV. EDMA: a computer program for topological analysis of discrete electron densities. J Appl Crystallogr. 2012;45:575–80.

    Article  CAS  Google Scholar 

  39. Sheldrick GM. A short history of SHELX. Acta Crystallogr A. 2008;64:112–22.

    Article  CAS  PubMed  Google Scholar 

  40. Ye YH, Ma L, Dai ZC, Xiao Y, Zhang YY, Li DD, et al. Synthesis and antifungal activity of nicotinamide derivatives as succinate dehydrogenase inhibitors. J Agric Food Chem. 2014;62:4063–71.

    Article  CAS  PubMed  Google Scholar 

  41. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30:2785–91.

  43. Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model. 1999;17:57–61.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant No. 42107020) and the Chunhui Programs of the Ministry of Education (No. 191653).

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  1. These authors contributed equally: Jingwen Wang, Tingting Xiao

Authors and Affiliations

  1. School of Science, Xihua University, Chengdu, 610039, China

    Jingwen Wang, Tingting Xiao, Tong Lu, Tingting Zhang, Wenjing Jiang, Yingkun Yan & Xiaorong Tang

  2. Guangdong Provincial Key Laboratory of Chemical Measurement and Emergency Test Technology, Guangdong Provincial Engineering Research Center for Ambient Mass Spectrometry, Institute of Analysis, Guangdong Academy of Sciences (China National Analytical Center, Guangzhou), Guangzhou, 510070, China

    Xuesong Wang

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Wang, J., Xiao, T., Lu, T. et al. Novel pyran derivatives as potential succinate dehydrogenase inhibitors: design, synthesis, crystal structure, biological activity, and molecular modeling. Med Chem Res 31, 1990–2006 (2022). https://doi.org/10.1007/s00044-022-02965-0

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