Combinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput Screening1386-20731875-5402Bentham Science64449010.2174/0113862073252234231017062643ChemistryResearch ArticleCombinatorial Synthesis of Indole Derivatives as Anti-oomycetes AgentsHaiFeiinfo@benthamscience.netWeiRuxueinfo@benthamscience.netLiYaninfo@benthamscience.netWangRuiguanginfo@benthamscience.netTianYueeinfo@benthamscience.netLiuShengminginfo@benthamscience.netChenGenqianginfo@benthamscience.netCheZhipinginfo@benthamscience.netCollege of Agricultural Engineering, Henan Vocational College of AgricultureLaboratory of Pesticidal Design & Synthesis, Department of Plant Protection, College of Horticulture and Plant Protection, Henan University of Science and TechnologyLaboratory of Pesticidal Design & Synthesis, Department of Plant Protection, College of Horticulture and Plant Protection,, Henan University of Science and Technology0110202427192816282307012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjpbr.com/1386-2073/article/view/644490

Background:Developing high-efficiency and low-risk small-molecule green fungicide is the key to effective control of the plant pathogenic oomycetes. Indole is an important raw material for drug synthesis. Due to its unique structural skeleton, indole, and its derivatives have exhibited a wide range of biological activities. However, a study on the synthesis of novel indole derivatives as fungicidal agents against Phytophthora capsici has not yet been reported.

Methods:The important intermediates 2a-c and 3a-c were synthesized in high yields by Vilsmeier- Haack and Knoevenagel reactions with indole as the lead compound. Furthermore, different substituted benzenesulfonyl groups were introduced into the NH position of the indole ring, and twelve indole derivatives (I-a-l) were prepared. Their structures were well characterized by 1H NMR, HRMS, and melting point.

Results:The results showed that 2-[(N-(4-nitrobenzenesulfonyl)-indole-3)-methylene]-diethyl malonate (I-d) and 2-[(N-(4-nitrobenzenesulfonyl)-5-cyanoindole-3)-methylene]-diethyl malonate (I-l) showed more anti-oomycete activity against P. capsici than the commercialized fungicide zoxamide, with corresponding EC50 values of 26.53, 23.48 and 28.16 mg/L, respectively, and the protective effect of the compounds against P. capsici in vivo further confirmed the above results.

Conclusion:The preliminary structure-activity relationship showed that the formyl group modification at the C-3 position of the indole ring was acceptable, and the different anti-oomycete activities of R1 and R2 were significantly different, with R1 being 5-CN > H > 6-Me, and R2 being 4-NO2 > 3-NO2, H > 4-Me.

Natural productindole synthesisanti-oomycete activityPhytophthora capsiciindole derivativesplant secondary metabolites.Savary, S.; Willocquet, L. Modeling the impact of crop diseases on global food security. Annu. Rev. Phytopathol., 2020, 58(1), 313-341. doi: 10.1146/annurev-phyto-010820-012856 PMID: 32511041Shimizu, T.; Miyashita, M. Frontiers of pesticide science in terms of the mode of action. J. Pestic. Sci., 2011, 36(4), 510. doi: 10.1584/jpestics.W11-33Masi, M.; Nocera, P.; Reveglia, P.; Cimmino, A.; Evidente, A. Fungal metabolites antagonists towards plant pests and human pathogens: Structure-activity relationship studies. Molecules, 2018, 23(4), 834. doi: 10.3390/molecules23040834 PMID: 29621148Miresmailli, S.; Isman, M.B. Botanical insecticides inspired by plant–herbivore chemical interactions. Trends Plant Sci., 2014, 19(1), 29-35. doi: 10.1016/j.tplants.2013.10.002 PMID: 24216132Sparks, T.C.; Hahn, D.R.; Garizi, N.V. Natural products, their derivatives, mimics and synthetic equivalents: Role in agrochemical discovery. Pest Manag. Sci., 2017, 73(4), 700-715. doi: 10.1002/ps.4458 PMID: 27739147Che, Z.; Guo, X.; Li, Y.; Zhang, S.; Zhu, L.; He, J.; Sun, D.; Guo, Y.; Liu, Y.; Wei, R.; Huang, X.; Liu, S.; Chen, G.; Tian, Y. Synthesis of paeonol ester derivatives and their insecticidal, nematicidal, and anti‐oomycete activities. Pest Manag. Sci., 2022, 78(8), 3442-3455. doi: 10.1002/ps.6985 PMID: 35567371Austin, J.F.; MacMillan, D.W.C. Enantioselective organocatalytic indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis. J. Am. Chem. Soc., 2002, 124(7), 1172-1173. doi: 10.1021/ja017255c PMID: 11841277Lamour, K.H.; Stam, R.; Jupe, J.; Huitema, E. The oomycete broad-host-range pathogen Phytophthora capsici. Mol. Plant Pathol., 2012, 13(4), 329-337. doi: 10.1111/j.1364-3703.2011.00754.x PMID: 22013895Meitz, J.C.; Linde, C.C.; Thompson, A.; Langenhoven, S.; McLeod, A. Phytophthora capsici on vegetable hosts in South Africa: Distribution, host range and genetic diversity. Australas. Plant Pathol., 2010, 39(5), 431-439. doi: 10.1071/AP09075Hausbeck, M.K.; Lamour, K.H. Phytophthora capsici on vegetable crops: Research progress and management challenges. Plant Dis., 2004, 88(12), 1292-1303. doi: 10.1094/PDIS.2004.88.12.1292 PMID: 30795189Lamour, K.H.; Hausbeck, M.K. The dynamics of mefenoxam insensitivity in a recombining population of Phytophthora capsici characterized with amplified fragment length polymorphism markers. Phytopathology, 2001, 91(6), 553-557. doi: 10.1094/PHYTO.2001.91.6.553 PMID: 18943943Parra, G.; Ristaino, J.B. Resistance to mefenoxam and metalaxyl among field isolates of Phytophthora capsici causing Phytophthora blight of bell pepper. Plant Dis., 2001, 85(10), 1069-1075. doi: 10.1094/PDIS.2001.85.10.1069 PMID: 30823278Che, Z.P.; Liu, S.M.; Wei, S.L.; Chen, G.Q. Synthesis and antifungal activities of 3-formylindoles against Exserohilum turcicum and Helminthosporium maydis in vitro. Agrochemicals, 2015, 54(3), 177-179.Chen, G.Q.; Che, Z.P.; Tian, Y.E.; Liu, S.M.; Xu, J.Q.; Cui, L.K.; Wei, S.L. Antifungal activities of substituted indole-3-carboxaldehyde derivatives. Modern Agrochemicals, 2016, 15(5), 12-14.Tian, Y.E.; Che, Z.P.; Liu, S.M.; Xia, Y.F.; Yang, C.G.; Hu, M.; Chen, G.Q. Antifungal activities of 2-(N-arylsulfonylindol-3-yl)-3-N-acyl-5-phenyl-1,3,4-oxadiazolines. Modern Agrochemicals, 2018, 17(4), 8-11.Dayan, F.E.; Cantrell, C.L.; Duke, S.O. Natural products in crop protection. Bioorg. Med. Chem., 2009, 17(12), 4022-4034. doi: 10.1016/j.bmc.2009.01.046 PMID: 19216080Tian, Y.E.; Sun, D.; Han, X.X.; Yang, J.M.; Zhang, S.; Feng, N.N.; Zhu, L.N.; Xu, Z.Y.; Che, Z.P.; Liu, S.M.; Lin, X.M.; Jiang, J.; Chen, G.Q. Synthesis, anti-oomycete activity, and SAR studies of paeonol derivatives. J. Asian Nat. Prod. Res., 2021, 23(2), 138-149. doi: 10.1080/10286020.2020.1718116 PMID: 32009450Che, Z.; Li, Y.; Guo, X.; He, J.; Zhang, S.; Zhu, L.; Liu, Y.; Wei, R.; Yang, Y.; Huang, X.; Liu, S.; Chen, G.; Tian, Y. Synthesis and anti-oomycete activity of sulfonate derivatives of Fenjuntong. Chem. Biodivers., 2022, 19(4), e202101039. doi: 10.1002/cbdv.202101039 PMID: 35261147Tian, Y.E.; Sun, D.; Yang, J.M.; Che, Z.P.; Liu, S.M.; Lin, X.M.; Jiang, J.; Chen, G.Q. Synthesis of sulfonate derivatives of maltol and their biological activity against Phytophthora capsici and Bursaphelenchus xylophilus in vitro. J. Asian Nat. Prod. Res., 2020, 22(6), 578-587. doi: 10.1080/10286020.2019.1608958 PMID: 31046458Xing, P.; Che, Z.; Liu, Y.; He, J.; Wei, R.; Chen, L.; Zhang, S.; Huang, X.; Yang, Y.; Liu, S.; Chen, G.; Tian, Y. Synthesis and anti-oomycete preliminary mechanism of sulfonate derivatives of ethyl maltol. Chem. Biodivers., 2022, 19(6), e202200255. doi: 10.1002/cbdv.202200255 PMID: 35560978Che, Z.; Zhang, S.; He, J.; Sun, D.; Guo, X.; Li, Y.; Zhu, L.; Guo, Y.; Liu, Y.; Tian, Y.; Huang, X.; Liu, S.; Chen, G. Combinatorial synthesis of sulfonate derivatives of α/β-naphthol as anti-oomycetes agents. Comb. Chem. High T. Scr., 2022, 25(12), 2026-2032. PMID: 35088660Chen, G.; Zhu, L.; He, J.; Zhang, S.; Li, Y.; Guo, X.; Sun, D.; Tian, Y.; Liu, S.; Huang, X.; Che, Z. Combinatorial synthesis of novel 1-sulfonyloxy/acyloxyeugenol derivatives as fungicidal agents. Comb. Chem. High T. Scr., 2022, 25(9), 1545-1551. PMID: 34391376Chen, G.; Zhu, L.; He, J.; Zhang, S.; Li, Y.; Guo, X.; Sun, D.; Tian, Y.; Liu, S.; Huang, X.; Che, Z. Synthesis and anti-oomycete activity of 1-sulfonyloxy/acyloxydihydroeugenol derivatives. Chem. Biodivers., 2021, 18(9), e2100329. doi: 10.1002/cbdv.202100329 PMID: 34346150Chen, G.Q.; Sun, D.; Yang, J.M.; Zhang, S.; Tian, Y.E.; Che, Z.P.; Liu, S.M.; Jiang, J.; Lin, X.M. Synthesis of sulfonate derivatives of carvacrol and thymol as anti-oomycetes agents. J. Asian Nat. Prod. Res., 2021, 23(7), 692-702. doi: 10.1080/10286020.2020.1758675 PMID: 32406756Che, Z.; Liu, Y.; Chen, L.; Xing, P.; Li, X.; Huang, X.; Liu, S.; Chen, G.; Lin, X.; Tian, Y. Synthesis of hinokitiol sulfonate derivatives and their anti-oomycete and nematicidal activities. Chem. Biodivers., 2022, 19(9), e202200580. doi: 10.1002/cbdv.202200580 PMID: 35975883Ge, Y.H.; Wu, Y.M.; Xue, Z.J. Synthesis of substituted indole-3-carboxaidehyde derivatives. Youji Huaxue, 2006, 26(4), 563-567.Nishimura, T.; Yamada, K.; Takebe, T.; Yokoshima, S.; Fukuyama, T. (1-nosyl-5-nitroindol-3-yl)methyl ester: A novel protective group for carboxylic acids. Org. Lett., 2008, 10(12), 2601-2604. doi: 10.1021/ol8008655 PMID: 18484732Che, Z.; Zhang, S.; Shao, Y.; Fan, L.; Xu, H.; Yu, X.; Zhi, X.; Yao, X.; Zhang, R. Synthesis and quantitative structure-activity relationship (QSAR) study of novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives as nematicidal agents. J. Agric. Food Chem., 2013, 61(24), 5696-5705. doi: 10.1021/jf400536q PMID: 23738496Deng, G.; Li, W.; Shen, J.; Jiang, H.; Chen, K.; Liu, H. Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: Virtual screening, synthesis, and biological evaluation. Bioorg. Med. Chem. Lett., 2008, 18(20), 5497-5502. doi: 10.1016/j.bmcl.2008.09.027 PMID: 18815030McNab, H.; Tyas, R.G. A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones. J. Org. Chem., 2007, 72(23), 8760-8769. doi: 10.1021/jo0712502 PMID: 17949040Peng, J.N.; Zhang, H.Z.; Li, C.L.; Li, X.H.; Qi, Z.Q. Antifungal activity of compound1S,2R-((3-bromophenethyl)amino)-N-(4-chloro-2-trifluoromethylphenyl) cyclohexane-1-sulfonamide against Botrytis cinerea and its mode of action. Chin. J. Pestic. Sci, 2021, 23(3), 509-514.Tian, Y.; Che, Z.; Sun, D.; He, J.; Liu, S.; Lin, X. In vitro effects of five different classes of fungicides on growth and development of Botrytis cinerea isolated from tree peony in China. HortScience, 2019, 54(11), 1984-1988. doi: 10.21273/HORTSCI14431-19Tian, Y.; Che, Z.; Sun, D.; Yang, Y.; Lin, X.; Liu, S.; Liu, X.; Gao, J. Resistance identification of tree peony varieties of different flowering time to gray mold pathogen Botrytis cinerea. HortScience, 2019, 54(2), 328-330. doi: 10.21273/HORTSCI13626-18