Design, Synthesis, Insecticidal Evaluation and Modeling Studies on 1,4,6,7- tetrahydropyrazolo[3,4-d][1,3]oxazine Derivatives: An Application of Scaffold Hopping Strategy on Fipronil

Guanglong       Li; Cong       Zhou; Chengchun       Zhu; Lujue       He; Xiaoyang       Li; Zhiping       Xu; Xiaoyong       Xu; Xusheng       Shao; Zhong       Li; Jiagao       Cheng

doi:10.2174/1570180816666190701101734

Abstract

Background: As the first phenylpyrazole pesticide, fipronil has been widely used in crop protection and public hygiene. In the low energy conformation of fipronil, a pseudo-six-membered ring is observed through an intramolecular hydrogen bond.

Methods: A scaffold hopping strategy was applied to mimic the pseudo-six-membered ring of fipronil by non-aromatic ring. All compounds were synthesized with a proper synthetic route and characterized by 1H NMR, 13C NMR and high-resolution mass spectra. Insecticidal activities of all target compounds against Plutella xylostella were assessed by a professional organization. Physicochemical property prediction and docking study of these compounds with GABA receptor were also performed.

Results: A series of 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine derivatives containing twenty-five compounds were designed, synthesized and evaluated. Several compounds exhibited moderate activities against Plutella xylostella. The strong electron-withdrawing groups are conducive to improve activities of this series of compounds against Plutella xylostella. Docking study showed that the most active compound 10 with nitro group could bind within the TM2 domain of GABA receptor, in which a hydrogen bond was observed with residue 6’Thr. The activity of 10 was weaker than fipronil due to the differences in physicochemical properties.

Conclusion: More attention should be paid to physicochemical properties during novel pesticide hit or lead design through scaffold hopping.

Keywords: Scaffold hopping, fipronil, low energy conformation, insecticidal activity, molecular modeling, GABA receptors.

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[1] 
Klis, S.F.L.; Vijverberg, H.P.M.; Bercken, J.V.D. Phenylpyrazoles, a new class of pesticides: An electrophysiological investigation into basic effects. Pestic. Biochem. Physiol.,  1991, 39, 210-218.
[http://dx.doi.org/10.1016/0048-3575(91)90116-4] 
[2] 
Chen, L.; Durkin, K.A.; Casida, J.E. Structural model for γ-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site. Proc. Natl. Acad. Sci. USA,  2006, 103(13), 5185-5190.
[http://dx.doi.org/10.1073/pnas.0600370103] [PMID:  16537435] 
[3] 
Casida, J.E. Insecticide action at the GABA-gated chloride channel: Recognition, progress, and prospects. Arch. Insect Biochem. Physiol.,  1993, 22(1-2), 13-23.
[http://dx.doi.org/10.1002/arch.940220104] [PMID:  7679302] 
[4] 
Cole, L.M.; Nicholson, R.A.; Casida, J.E. Action of phenylpyrazole insecticides at the GABA-gated chloride channel. Pestic. Biochem. Physiol.,  1993, 46, 47-54.
[http://dx.doi.org/10.1006/pest.1993.1035] 
[5] 
Tingle, C.C.D.; Rother, J.A.; Dewhurst, C.F.; Lauer, S.; King, W.J. Fipronil: environmental fate, ecotoxicology, and human health concerns. Rev. Environ. Contam. Toxicol.,  2003, 176, 1-66.
[http://dx.doi.org/10.1007/978-1-4899-7283-5_1] [PMID:  12442503] 
[6] 
Aajoud, A.; Ravanel, P.; Tissut, M. Fipronil metabolism and dissipation in a simplified aquatic ecosystem. J. Agric. Food Chem.,  2003, 51(5), 1347-1352.
[http://dx.doi.org/10.1021/jf025843j] [PMID:  12590480] 
[7] 
Moffat, A.S. New chemicals seek to outwit insect pests. Science,  1993, 261(5121), 550-551.
[http://dx.doi.org/10.1126/science.8393587] [PMID:  8393587] 
[8] 
Ozoe, Y.; Akamatsu, M. Non-competitive GABA antagonists: Probing the mechanisms of their selectivity for insect versus mammalian receptors. Pest Manag. Sci.,  2001, 57(10), 923-931.
[http://dx.doi.org/10.1002/ps.375] [PMID:  11695185] 
[9] 
Ratra, G.S.; Kamita, S.G.; Casida, J.E. Role of human GABA(A) receptor β3 subunit in insecticide toxicity. Toxicol. Appl. Pharmacol.,  2001, 172(3), 233-240.
[http://dx.doi.org/10.1006/taap.2001.9154] [PMID:  11312652] 
[10] 
Wu, T.T. Pesticidal 5-amino-4-ethylsulfinyl-1-arylpyrazoles. U.S. Patent 5,814,652, September 29, 1998.
[11] 
Sheng, C.W.; Casida, J.E.; Durkin, K.A.; Chen, F.; Han, Z.J.; Zhao, C.Q. Fiprole insecticide resistance of Laodelphax striatellus: Electrophysiological and molecular docking characterization of A2'N RDL GABA receptors. Pest Manag. Sci.,  2018, 74(11), 2645-2651.
[http://dx.doi.org/10.1002/ps.5059] [PMID:  29718557] 
[12] 
Stehr, C.M.; Linbo, T.L.; Incardona, J.P.; Scholz, N.L. The developmental neurotoxicity of fipronil: Notochord degeneration and locomotor defects in zebrafish embryos and larvae. Toxicol. Sci.,  2006, 92(1), 270-278.
[http://dx.doi.org/10.1093/toxsci/kfj185] [PMID:  16611622] 
[13] 
Wang, X.; Zhou, S.; Ding, X.; Zhu, G.; Guo, J. Effect of triazophos, fipronil and their mixture on miRNA expression in adult zebrafish. J. Environ. Sci. Health B,  2010, 45(7), 648-657.
[http://dx.doi.org/10.1080/03601234.2010.502435] [PMID:  20818518] 
[14] 
Roat, T.C.; Carvalho, S.M.; Palma, M.S.; Malaspina, O. Biochemical response of the Africanized honeybee exposed to fipronil. Environ. Toxicol. Chem.,  2017, 36(6), 1652-1660.
[http://dx.doi.org/10.1002/etc.3699] [PMID:  27925273] 
[15] 
Nicodemo, D.; Maioli, M.A.; Medeiros, H.C.D.; Guelfi, M.; Balieira, K.V.B.; De Jong, D.; Mingatto, F.E. Fipronil and imidacloprid reduce honeybee mitochondrial activity. Environ. Toxicol. Chem.,  2014, 33(9), 2070-2075.
[http://dx.doi.org/10.1002/etc.2655] [PMID:  25131894] 
[16] 
Zheng, N.; Cheng, J.; Zhang, W.; Li, W.; Shao, X.; Xu, Z.; Xu, X.; Li, Z. Binding difference of fipronil with GABAARs in fruitfly and zebrafish: insights from homology modeling, docking, and molecular dynamics simulation studies. J. Agric. Food Chem.,  2014, 62(44), 10646-10653.
[http://dx.doi.org/10.1021/jf503851z] [PMID:  25302733] 
[17] 
Zhang, B.; Zhang, L.; He, L.; Yang, X.; Shi, Y.; Liao, S.; Yang, S.; Cheng, J.; Ren, T. Interactions of fipronil within fish and insects: Experimental and molecular modeling studies. J. Agric. Food Chem.,  2018, 66(23), 5756-5761.
[http://dx.doi.org/10.1021/acs.jafc.8b00573] [PMID:  29627978] 
[18] 
Lamberth, C. Agrochemical lead optimization by scaffold hopping. Pest Manag. Sci.,  2018, 74(2), 282-292.
[http://dx.doi.org/10.1002/ps.4755] [PMID:  28991418] 
[19] 
Sakamuri, S.; Chen, Q.Z.; Lu, Y.C.; Keng, Y.F.; Khazak, V.; Illgen, K.; Schabbert, S.; Weber, L.; Menon, S.R. Initial design and synthesis of conformationally restricted and pharmacophore-based scaffold hopping analogs of a ras pathway modulator and evaluation of their MAPK inhibitory activities. Lett. Drug Des. Discov.,  2006, 3, 44-48.
[http://dx.doi.org/10.2174/157018006775240890] 
[20] 
Anan, K.; Masui, M.; Hara, S.; Ohara, M.; Kume, M.; Yamamoto, S.; Shinohara, S.; Tsuji, H.; Shimada, S.; Yagi, S.; Hasebe, N.; Kai, H. Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach. Bioorg. Med. Chem. Lett.,  2017, 27(17), 4194-4198.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.076] [PMID:  28754363] 
[21] 
Kumar, A.; Ito, A.; Hirohama, M.; Yoshida, M.; Zhang, K.Y.J. Identification of new SUMO activating enzyme 1 inhibitors using virtual screening and scaffold hopping. Bioorg. Med. Chem. Lett.,  2016, 26(4), 1218-1223.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.030] [PMID:  26810265] 
[22] 
Nishigaya, Y.; Umei, K.; Saito, Y.; Watanabe, H.; Kondo, T.; Kondo, A.; Kawamura, N.; Tatani, K.; Kohno, Y.; Tanaka, N.; Seto, S. Discovery of novel pyrazolo[1,5-a]pyridine-based EP1 receptor antagonists by scaffold hopping: Design, synthesis, and structure-activity relationships. Bioorg. Med. Chem. Lett.,  2017, 27(17), 4044-4050.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.055] [PMID:  28784294] 
[23] 
Li, K.J.; Qu, R.Y.; Liu, Y.C.; Yang, J.F.; Devendar, P.; Chen, Q.; Niu, C.W.; Xi, Z.; Yang, G.F. Design, synthesis, and herbicidal activity of pyrimidine-biphenyl hybrids as novel acetohydroxyacid synthase inhibitors. J. Agric. Food Chem.,  2018, 66(15), 3773-3782.
[http://dx.doi.org/10.1021/acs.jafc.8b00665] [PMID:  29618205] 
[24] 
Crowley, P.J.; Lamberth, C.; Müller, U.; Wendeborn, S.; Nebel, K.; Williams, J.; Sageot, O.A.; Carter, N.; Mathie, T.; Kempf, H.J.; Godwin, J.; Schneiter, P.; Dobler, M.R. Synthesis and fungicidal activity of tubulin polymerisation promoters. Part 1: pyrido[2,3-b]pyrazines. Pest Manag. Sci.,  2010, 66(2), 178-185.
[PMID:  19795441] 
[25] 
Taggi, A.E.; Stevenson, T.M.; Bereznak, J.F.; Sharpe, P.L.; Gutteridge, S.; Forman, R.; Bisaha, J.J.; Cordova, D.; Crompton, M.; Geist, L.; Kovacs, P.; Marshall, E.; Sheth, R.; Stavis, C.; Tseng, C.P. Tubulin modulating antifungal and antiproliferative pyrazinone derivatives. Bioorg. Med. Chem.,  2016, 24(3), 435-443.
[http://dx.doi.org/10.1016/j.bmc.2015.08.038] [PMID:  26386818] 
[26] 
Zhang, L.; Li, W.; Xiao, T.; Song, Z.; Csuk, R.; Li, S. Design and discovery of novel chiral antifungal amides with 2-(2-oxazolinyl)aniline as a promising pharmacophore. J. Agric. Food Chem.,  2018, 66(34), 8957-8965.
[http://dx.doi.org/10.1021/acs.jafc.8b02778] [PMID:  30092640] 
[27] 
Sulzer-Mosse, S.; Cederbaum, F.; Lamberth, C.; Berthon, G.; Umarye, J.; Grasso, V.; Schlereth, A.; Blum, M.; Waldmeier, R. Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new family of anti-oomycete compounds. Bioorg. Med. Chem.,  2015, 23(9), 2129-2138.
[http://dx.doi.org/10.1016/j.bmc.2015.03.007] [PMID:  25801153] 
[28] 
Lahm, G.P.; Cordova, D.; Barry, J.D. New and selective ryanodine receptor activators for insect control. Bioorg. Med. Chem.,  2009, 17(12), 4127-4133.
[http://dx.doi.org/10.1016/j.bmc.2009.01.018] [PMID:  19186058] 
[29] 
Lamberth, C.; Jeanguenat, A.; Cederbaum, F.; De Mesmaeker, A.; Zeller, M.; Kempf, H.J.; Zeun, R. Multicomponent reactions in fungicide research: The discovery of mandipropamid. Bioorg. Med. Chem.,  2008, 16(3), 1531-1545.
[http://dx.doi.org/10.1016/j.bmc.2007.10.019] [PMID:  17962029] 
[30] 
Pasteris, R.J.; Hanagan, M.A.; Bisaha, J.J.; Finkelstein, B.L.; Hoffman, L.E.; Gregory, V.; Andreassi, J.L.; Sweigard, J.A.; Klyashchitsky, B.A.; Henry, Y.T.; Berger, R.A. Discovery of oxathiapiprolin, a new oomycete fungicide that targets an oxysterol binding protein. Bioorg. Med. Chem.,  2016, 24(3), 354-361.
[http://dx.doi.org/10.1016/j.bmc.2015.07.064] [PMID:  26314923] 
[31] 
Xu, Y.; Yang, X.; Chen, Y.; Chen, H.; Sun, H.; Li, W.; Xie, Q.; Yu, L.; Shao, L. Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib. Bioorg. Med. Chem. Lett.,  2018, 28(12), 2148-2152.
[http://dx.doi.org/10.1016/j.bmcl.2018.05.018] [PMID:  29773504] 
[32] 
Guo, X.Y.; Liu, G. Scaffold-hopping strategy toward calanolides with nitrogen-containing heterocycles. Chin. Chem. Lett.,  2013, 24, 295-298.
[http://dx.doi.org/10.1016/j.cclet.2013.03.007] 
[33] 
Shao, X.; Lee, P.W.; Liu, Z.; Xu, X.; Li, Z.; Qian, X. cis-Configuration: a new tactic/rationale for neonicotinoid molecular design. J. Agric. Food Chem.,  2011, 59(7), 2943-2949.
[http://dx.doi.org/10.1021/jf103499x] [PMID:  21043520] 
[34] 
Zhang, W.; Chen, Y.; Chen, W.; Liu, Z.; Li, Z. Designing Tetrahydroimidazo[1,2-a]pyridine derivatives via catalyst-free Aza-Diels-Alder reaction (ADAR) and their insecticidal evaluation. J. Agric. Food Chem.,  2010, 58(10), 6296-6299.
[http://dx.doi.org/10.1021/jf100645y] [PMID:  20423095] 
[35] 
Tian, Z.; Shao, X.; Li, Z.; Qian, X.; Huang, Q. Synthesis, insecticidal activity, and QSAR of novel nitromethylene neonicotinoids with tetrahydropyridine fixed cis configuration and exo-ring ether modification. J. Agric. Food Chem.,  2007, 55(6), 2288-2292.
[http://dx.doi.org/10.1021/jf063418a] [PMID:  17311404] 
[36] 
Tian, Z.; Jiang, Z.; Li, Z.; Song, G.; Huang, Q. Syntheses and biological activities of octahydro-1H-cyclopenta[d]pyrimidine derivatives. J. Agric. Food Chem.,  2007, 55(1), 143-147.
[http://dx.doi.org/10.1021/jf062845l] [PMID:  17199325] 
[37] 
Shao, X.; Fu, H.; Xu, X.; Xu, X.; Liu, Z.; Li, Z.; Qian, X. Divalent and oxabridged neonicotinoids constructed by dialdehydes and nitromethylene analogues of imidacloprid: Design, synthesis, crystal structure, and insecticidal activities. J. Agric. Food Chem.,  2010, 58(5), 2696-2702.
[http://dx.doi.org/10.1021/jf902531y] [PMID:  20000569] 
[38] 
Shao, X.; Xu, Z.; Zhao, X.; Xu, X.; Tao, L.; Li, Z.; Qian, X. Synthesis, crystal structure, and insecticidal activities of highly congested hexahydroimidazo[1,2-a]pyridine derivatives: effect of conformation on activities. J. Agric. Food Chem.,  2010, 58(5), 2690-2695.
[http://dx.doi.org/10.1021/jf902513t] [PMID:  20000414] 
[39] 
Shao, X.; Li, Z.; Qian, X.; Xu, X. Design, synthesis, and insecticidal activities of novel analogues of neonicotinoids: Replacement of nitromethylene with nitroconjugated system. J. Agric. Food Chem.,  2009, 57(3), 951-957.
[http://dx.doi.org/10.1021/jf803305f] [PMID:  19138119] 
[40] 
Taillebois, E.; Alamiddine, Z.; Brazier, C.; Graton, J.; Laurent, A.D.; Thany, S.H.; Le Questel, J.Y. Molecular features and toxicological properties of four common pesticides, acetamiprid, deltamethrin, chlorpyriphos and fipronil. Bioorg. Med. Chem.,  2015, 23(7), 1540-1550.
[http://dx.doi.org/10.1016/j.bmc.2015.02.006] [PMID:  25716006] 
[41] 
Zalucki, M.P.; Shabbir, A.; Silva, R.; Adamson, D.; Shu-Sheng, L.; Furlong, M.J. Estimating the economic cost of one of the world’s major insect pests, Plutella xylostella (Lepidoptera: Plutellidae): just how long is a piece of string? J. Econ. Entomol.,  2012, 105(4), 1115-1129.
[http://dx.doi.org/10.1603/EC12107] [PMID:  22928287] 

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DOI https://dx.doi.org/10.2174/1570180816666190701101734	Print ISSN 1570-1808
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Design, Synthesis, Insecticidal Evaluation and Modeling Studies on 1,4,6,7- tetrahydropyrazolo[3,4-d][1,3]oxazine Derivatives: An Application of Scaffold Hopping Strategy on Fipronil

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