Generic placeholder image

Current Organic Chemistry


ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Research Article

Synthesis and Reactions of Fused Pyrazolo[3,4-b]Pyridine Derivatives: Insecticidal Activity and Digestive Dysfunction against Mosquito Larvae

Author(s): Ahmed A.O. Abeed*, Talaat I. El-Emary, Mohamed S.K. Youssef, Ibrahim Hefzy and Ahmed M.A. Ibrahim

Volume 27, Issue 10, 2023

Published on: 31 August, 2023

Page: [852 - 859] Pages: 8

DOI: 10.2174/1385272827666230804112116

Price: $65


5-Amino-4-formyl pyrazole 1 was used as a precursor for the synthesis of 6- aminopyrazolo[3,4-b]pyridine-5-carbonitrile 2, and 6-aminopyrazolo[3,4-b]pyridine-5- carboxamides 3 and 4. Pyrazolo[3,4-b]pyridines 2, 3, and 4 were treated with different reagents leading to structurally confirmed heterocycles. Mosquito adult females carry and transmit the causatives of many diseases to humans and other domestic animals. Therefore, their management has become a necessity. Ten of the synthesized compounds were tested for larvicidal activity against second-stage C. pipiens larvae.

IR spectra were recorded on Shimadzu-408 infrared spectrophotometer. The NMR spectra were performed on a Bruker AV-400 spectrometer and JEOL ECA II 500 MHz. Mass spectrometry was provided on a Varian MAT 312 instrument in EI mode (70 eV). Lethal concentrations were calculated based on probit analysis. Biochemical enzymes were analyzed using analysis of variance ANOVA with Graph Pad Prism 5. Mean comparisons were analyzed using Tukey's test.

Five compounds, 1, 2, 4, 5 and 11 exhibited detectable insecticidal activity as these compounds recorded 154.4, 5.6x103, 8.4, 135.1 and 697.2 ppm, respectively. Moreover, the effect of these insecticidal compounds on lipids and carbohydrates digestive pathways in the larvae was evaluated by comparing the activities of amylase and lipase digestive enzymes in both control and treated larvae. Compounds 1, 4 and 5 showed an inhibitory effect on both lipase and amylase enzymes. Compound 2 inhibited lipase activity, while compound 11 didn’t affect both enzymes compared with the control.

Results showed that the incorporation of pyridine and pyrazole induced significant insecticidal activity against larval mosquitoes. Furthermore, insertion of amino or carbonyl groups into the synthesized compounds enhanced the insecticidal activity. Our findings showed that development of such novel compounds is promising in enhancing the agricultural productivity and management of diseases transmitted by insects.

Keywords: Pyrazolo[3, 4-b]pyridines, heterocycles, insecticidal activity, biochemical impact, digestive dysfunction, mosquito larvae, vector management.

Graphical Abstract
Wilkerson, R.C.; Linton, Y.M.; Fonseca, D.M.; Schultz, T.R.; Price, D.C.; Strickman, D.A. Making mosquito taxonomy useful: A stable classification of tribe aedini that balances utility with current knowledge of evolutionary relationships. PLoS One, 2015, 10(7), e0133602.
[] [PMID: 26226613]
Fontenille, D.; Diallo, M.; Mondo, M.; Ndiaye, M.; Thonnon, J. First evidence of natural vertical transmission of yellow fever virus in Aedes aegypti, its epidemic vector. Trans. R. Soc. Trop. Med. Hyg., 1997, 91(5), 533-535.
[] [PMID: 9463659]
Mayer, S.V.; Tesh, R.B.; Vasilakis, N. The emergence of arthropod-borne viral diseases: A global prospective on dengue, chikungunya and zika fevers. Acta Trop., 2017, 166, 155-163.
[] [PMID: 27876643]
Becker, N.; Petric, D.; Zgomba, M.; Boase, C.; Madon, M.; Dahl, C.; Kaiser, A. Mosquitoes and their control; Springer Science and Business Media, 2010, p. 577.
Hemingway, J.; Ranson, H. Insecticide resistance in insect vectors of human disease. Annu. Rev. Entomol., 2000, 45(1), 371-391.
[] [PMID: 10761582]
Li, H.; Zhao, Y.; Sun, P.; Gao, L.; Li, Y.; Xiong, L.; Yang, N.; Zhou, S.; Li, Z. Synthesis and insecticidal evaluation of novel anthranilicdiamides derivatives containing 4-chlorine substituted n-pyridylpyrazole. Chin. J. Chem., 2021, 39(1), 75-80.
Wang, B.; Wang, H.; Liu, H.; Xiong, L.; Yang, N.; Zhang, Y.; Li, Z. Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic acid derivatives containing fluorine moiety. Chin. Chem. Lett., 2020, 31(3), 739-745.
Zhao, Q.; Sun, R.; Liu, Y.; Chen, P.; Li, Y.; Yang, S.; Wang, Q.; Rangappa, K.S. Synthesis and insecticidal activity studies of novel phenylpyrazole derivatives containing arylimine or carbimidate moiety. Bioorg. Med. Chem., 2019, 27(21), 115092.
[] [PMID: 31521460]
Alam, O.; Naim, M.J.; Nawaz, F.; Alam, M.J.; Alam, P. Current status of pyrazole and its biological activities. J. Pharm. Bioallied Sci., 2016, 8(1), 2-17.
[] [PMID: 26957862]
a) Abdu-Allah, H.H.M.; El-Emary, T.I. Synthesis and preliminary biological screening of 6-aminopyrazolo[3,4-b]pyridine derivatives. Pharma Chem., 2016, 8, 9-16.;
b) El-Emary, T.I. Synthesis of newly substituted pyrazoles and substituted pyrazolo[3,4-b]pyridines based on 5-amino-3-methyl-1-phenylpyrazole. J. Chin. Chem. Soc., 2007, 54(2), 507-518.
c) el-Emary, T.I.; Hussein, A.M.; el-Kashef, H.S. New polycyclic azines derived from pyrazolo[3,4-b]pyridine. Pharmazie, 2000, 55(5), 356-358.
[PMID: 11828614];
d) El-Emary, T.I. A convenient synthetic approach to newly condensed pyrazolo-azines based on pyrazolo[3,4-b]pyridine. J. Chin. Chem. Soc., 1999, 46(4), 585-590.
e) El-Emary, T.; El-Mohsen, S. Multi-component one-pot synthesis and antimicrobial activities of 3-methyl-1,4-diphenyl-7-thioxo-4,6,8,9-tetrahydro-pyrazolo[5,4-b]pyrimidino[5,4-e]pyridine-5-one and related derivatives. Molecules, 2012, 17(12), 14464-14483.
[] [PMID: 23222865];
f) Abdelmohsen, S.A.; Emary, T.I.E. Synthesis, characterization and antimicrobial activity of novel pyrazolo[3,4-b]pyridines and their spiro-heterocyclic derivatives. J. Adv. Chem, 2014, 10(7), 2901-2915.
g) Aly, A.A.; El-Emary, T.I.; Mourad, A.F.E.; Alyan, Z.K.; Bräse, S.; Nieger, M. Synthesis of new heterocycles from reactions of 1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl azides. J. Heterocycl. Chem., 2019, 56(4), 1369-1375.
h) Aly, A.A.; El-Emary, T.I.; Mourad, A.F.E.; Khallaf Alyan, Z.; Bräse, S.; Nieger, M. 5-Carbohydrazide and 5-carbonylazide of pyrazolo[3,4- b]pyridines as reactive intermediates in the synthesis of various heterocyclic derivatives. J. Chem. Res., 2019, 43(7-8), 219-229.
Pagadala, R.; Maddila, S.; Moodley, V.; van Zyl, W.E.; Jonnalagadda, S.B. An efficient method for the multicomponent synthesis of multisubstituted pyridines, a rapid procedure using Au/MgO as the catalyst. Tetrahedron Lett., 2014, 55(29), 4006-4010.
Kim, H.S.; Jadhav, J.R.; Jung, S.J.; Kwak, J.H. Synthesis and antimicrobial activity of imidazole and pyridine appended cholestane-based conjugates. Bioorg. Med. Chem. Lett., 2013, 23(15), 4315-4318.
[] [PMID: 23791571]
Bharate, S.B.; Mahajan, T.R.; Gole, Y.R.; Nambiar, M.; Matan, T.T.; Kulkarni-Almeida, A.; Balachandran, S.; Junjappa, H.; Balakrishnan, A.; Vishwakarma, R.A. Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-α and IL-6 inhibitors. Bioorg. Med. Chem., 2008, 16(15), 7167-7176.
[] [PMID: 18625560]
Chioua, M.; Samadi, A.; Soriano, E.; Lozach, O.; Meijer, L.; Marco-Contelles, J. Synthesis and biological evaluation of 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(16), 4566-4569.
[] [PMID: 19615897]
Huang, S.; Lin, R.; Yu, Y.; Lu, Y.; Connolly, P.J.; Chiu, G.; Li, S.; Emanuel, S.L.; Middleton, S.A. Synthesis of 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine, a potent cyclin dependent kinase 1 (CDK1) inhibitor. Bioorg. Med. Chem. Lett., 2007, 17(5), 1243-1245.
[] [PMID: 17234412]
Witherington, J.; Bordas, V.; Gaiba, A.; Garton, N.S.; Naylor, A.; Rawlings, A.D.; Slingsby, B.P.; Smith, D.G.; Takle, A.K.; Ward, R.W. 6-Aryl-pyrazolo[3,4-b]pyridines: Potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg. Med. Chem. Lett., 2003, 13(18), 3055-3057.
[] [PMID: 12941332]
Saggar, S.; Sisko, J.; Tucker, T.; Tynebor, R.; Su, D.; Anthony, N.U.S. Acoustic alert communication system with enhanced signal to noise. Chem. Abstr., 2007, 146, 163149.
Lin, R.; Connolly, P.J.; Lu, Y.; Chiu, G.; Li, S.; Yu, Y.; Huang, S.; Li, X.; Emanuel, S.L.; Middleton, S.A.; Gruninger, R.H.; Adams, M.; Fuentes-Pesquera, A.R.; Greenberger, L.M. Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents. Bioorg. Med. Chem. Lett., 2007, 17(15), 4297-4302.
[] [PMID: 17532631]
Ye, Q.; Cao, J.; Zhou, X.; Lv, D.; He, Q.; Yang, B.; Hu, Y. Synthesis and evaluation of novel 7-azaindazolyl-indolyl-maleimide derivatives as antitumor agents and protein kinase C inhibitors. Bioorg. Med. Chem., 2009, 17(13), 4763-4772.
[] [PMID: 19447039]
Leal, B.; Afonso, I.F.; Rodrigues, C.R.; Abreu, P.A.; Garrett, R.; Pinheiro, L.C.S.; Azevedo, A.R.; Borges, J.C.; Vegi, P.F.; Santos, C.C.C.; da Silveira, F.C.A.; Cabral, L.M.; Frugulhetti, I.C.P.P.; Bernardino, A.M.R.; Santos, D.O.; Castro, H.C. Antibacterial profile against drug-resistant Staphylococcus epidermidis clinical strain and structure–activity relationship studies of 1H-pyrazolo[3,4-b]pyridine and thieno[2,3-b]pyridine derivatives. Bioorg. Med. Chem., 2008, 16(17), 8196-8204.
[] [PMID: 18701299]
Goda, F.E.; Abdel-Aziz, A.A.M.; Attef, O.A. Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF3-promoted reaction of hydrazine with 2-alkoxy pyridines. Bioorg. Med. Chem., 2004, 12(8), 1845-1852.
[] [PMID: 15051053]
Foks, H.; Pancechowska-Ksepko, D. Kędzia, A.; Zwolska, Z.; Janowiec, M.; Augustynowicz-Kopeć E. Synthesis and antibacterial activity of 1H-pyrazolo[3,4-b]pyrazine and -pyridine derivatives. Farmaco, 2005, 60(6-7), 513-517.
[] [PMID: 15950227]
Bare, T.M.; McLaren, C.D.; Campbell, J.B.; Firor, J.W.; Resch, J.F.; Walters, C.P.; Salama, A.I.; Meiners, B.A.; Patel, J.B. Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents. J. Med. Chem., 1989, 32(12), 2561-2573.
[] [PMID: 2573731]
Xing, Y.; Zuo, J.; Krogstad, P.; Jung, M.E. Synthesis and structure-activity relationship (SAR) studies of novel pyrazolopyridine derivatives as inhibitors of enterovirus replication. J. Med. Chem., 2018, 61(4), 1688-1703.
[] [PMID: 29346733]
Chu, I.; Lynch, B.M. Synthesis and biological evaluation of xanthine oxidase inhibitors. Pyrazolo[3,4-d]pyrimidines and pyrazolo[3,4-b]pyridines. J. Med. Chem., 1975, 18(2), 161-165.
[] [PMID: 1120982]
Feurer, A.; Luithle, J.; Wirtz, S.; Koenig, G.; Stasch, J.; Stahl, E.; Schreiber, R.; Wunder, F.; Lang, D. PCT Intl. Appl. WO 2004009589. Chem. Abstr., 2004, 140, 146157.
Gudmundsson, K.S.; Johns, B.A.; Wang, Z.; Turner, E.M.; Allen, S.H.; Freeman, G.A.; Boyd, F.L., Jr; Sexton, C.J.; Selleseth, D.W.; Moniri, K.R.; Creech, K.L. Synthesis of novel substituted 2-phenylpyrazolopyridines with potent activity against herpesviruses. Bioorg. Med. Chem., 2005, 13(18), 5346-5361.
[] [PMID: 16039862]
Ohno, R.; Nagaoka, M.; Hirai, K.; Uchida, A.; Kochi, S.; Yamada, O.; Tokumura, J. Synthesis and insecticidal activity of novel 1-alkyl-3-sulfonyloxypyrazole-4-carboxamide derivatives. J. Pestic. Sci., 2010, 35(1), 15-22.
Wu, J.; Song, B.A.; Hu, D.Y.; Yue, M.; Yang, S. Design, synthesis and insecticidal activities of novel pyrazole amides containing hydrazone substructures. Pest Manag. Sci., 2012, 68(5), 801-810.
[] [PMID: 22190278]
Huang, D.; Liu, A.; Liu, W.; Liu, X.; Ren, Y.; Zheng, X.; Pei, H.; Xiang, J.; Huang, M.; Wang, X. Synthesis and insecticidal activities of novel 1 H -pyrazole-5-carboxylic acid derivatives. Heterocycl. Commun., 2017, 23(6), 455-460.
De, K.; Bhaumik, A.; Banerjee, B.; Mukhopadhyay, C. An expeditious and efficient synthesis of spiro-pyrazolo[3,4-b]pyridines catalysed by recyclable mesoporous aluminosilicate nanoparticles in aqueous-ethanol. Tetrahedron Lett., 2015, 56(13), 1614-1618.
a) Youssef, M.S.K.; Abeed, A.A.O. Synthesis, characterization and pharmacological activities of pyrimidine derivatives containing 2-pyrazolin-5-one. Int. J. Pharm., 2014, 5, 1705-1720.;
b) Youssef, M.S.K.; Omar, A.A. Synthesis and Reactions of 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile. Monatsh. Chem., 2007, 138(10), 989-995.
c) Youssef, M.S.K.; Abbady, M.S.; Ahmed, R.A.; Omar, A.A. Synthesis of some new heterocycles derived from ethyl 7-amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-aryl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate of Biological Importance. J. Heterocycl. Chem., 2013, 50(2), 179-187.
d) Youssef, M.S.K.; Abbady, M.S.; Ahmed, R.A.; Omar, A.A. Preparation and Reactions of 2-Methyl-7-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-5-arylthiazolo[3,2-a]-pyrimido[4,5-d]oxazin-4(5H)-one. Chin. J. Chem., 2011, 29(7), 1473-1482.
e) Abeed, A.A.O.; Youssef, M.S.K.; Hegazy, R. Synthesis, anti-diabetic and renoprotect-ive activity of some new benzazole, thiazolidin-4-one and azetidin-2-one derivatives. J. Braz. Chem. Soc., 2017, 28, 2054-2063.;
f) Youssef, M.S.K.; Abeed, A.A.O.; El-Emary, T.I. Synthesis and evaluation of chromene-based compounds containing pyrazole moiety as antimicrobial agents. Heterocycl. Commun., 2017, 23(1), 55-64.
g) Abeed, A.A.O.; Jaleel, G.A.A.; Youssef, M.S.K. Novel heterocyclic hybrids based on 2-pyrazoline: Synthesis and assessment of anti-inflammatory and analgesic activities. Curr. Org. Synth., 2019, 16(6), 921-930.
[] [PMID: 31984913];
h) Abeed, A.A.O.; El-Emary, T.; Alharthi, S. Efficient synthetic access to novel indolo[2,3-b]quinoxaline-based heterocycles. Curr. Org. Synth., 2022, 19(1), 177-185.
[] [PMID: 34370643]
Häufel, J.; Breitmaier, E. Synthesis of pyrazolo-heteroaromatic compounds by means of 5-amino-3-methyl-1-phenylpyrazole-4-carbaldehyde. Angew. Chem. Int. Ed. Engl., 1974, 13(9), 604-611.
Hussein, A.M.; El-Emary, T.I. Polycyclic pyrazoles: Routes to new pyrazoloazines. J. Chem. Res. Synop., 1998, 1(1), 20-21. [s].
Jiang, D.X.; Lu, X.L.; Hu, S.; Zhang, X-B.; Xu, H-H. A new derivative of fipronil: Effect of adding a glycinyl group to the 5-amine of pyrazole on phloem mobility and insecticidal activity. Pestic. Biochem. Physiol., 2009, 95(3), 126-130.
Haugwitz, R.D.; Martinez, A.J.; Venslavsky, J.; Angel, R.G.; Maurer, B.V.; Jacobs, G.A.; Narayanan, V.L.; Cruthers, L.R.; Szanto, J. Antiparasitic agents. 6. Synthesis and anthelmintic activities of novel isothiocyanatophenyl-1,2,4-oxadiazoles. J. Med. Chem., 1985, 28(9), 1234-1241.
[] [PMID: 4032426]
Liu, Q.; Zhu, R.; Gao, S.; Ma, S.H.; Tang, H.J.; Yang, J.J.; Diao, Y.M.; Wang, H.L.; Zhu, H.J. Structure-based bioisosterism design, synthesis, insecticidal activity and structure-activity relationship (SAR) of anthranilic diamide analogues containing 1,2,4-oxadiazole rings. Pest Manag. Sci., 2017, 73(5), 917-924.
[] [PMID: 27427282]
Yang, S.; Tian, X.Y.; Ma, T.Y.; Dai, L.; Ren, C.L.; Mei, J.C.; Liu, X.H.; Tan, C.X. Synthesis and biological activity of benzamides substituted with pyridine-linked 1,2,4-oxadiazole. Molecules, 2020, 25(15), 3500-3508.
[] [PMID: 32752024]
Richardson, E.B.; Troczka, B.J.; Gutbrod, O.; Davies, T.G.E.; Nauen, R. Diamide resistance: 10 years of lessons from lepidopteran pests. J. Pest Sci., 2020, 93(3), 911-928.
Kees, K.L.; Fitzgerald, J.J., Jr; Steiner, K.E.; Mattes, J.F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M.L. New potent antihyperglycemic agents in db/db mice: Synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem., 1996, 39(20), 3920-3928.
[] [PMID: 8831758]
Bansal, G.; Singh, S.; Monga, V.; Thanikachalam, P.V.; Chawla, P. Synthesis and biological evaluation of thiazolidine-2,4-dione-pyrazole conjugates as antidiabetic, anti-inflammatory and antioxidant agents. Bioorg. Chem., 2019, 92, 103271.
[] [PMID: 31536952]
Nidhar, M.; Sonker, P.; Sharma, V.P.; Kumar, S.; Tewari, A.K. Design, synthesis and in-silico & in vitro enzymatic inhibition assays of pyrazole-chalcone derivatives as dual inhibitors of α-amylase & DPP-4 enzyme. Chem. Zvesti, 2022, 76(3), 1707-1720.
S N C S.; Bhurta, D.; Kantiwal, D.; George, G.; Monga, V.; Paul, A.T. Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(16), 3749-3754.
[] [PMID: 28705641]
Aghazadeh Tabrizi, M.; Baraldi, P.G.; Ruggiero, E.; Saponaro, G.; Baraldi, S.; Romagnoli, R.; Martinelli, A.; Tuccinardi, T. Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH). Eur. J. Med. Chem., 2015, 97, 289-305.
[] [PMID: 26002335]
Ilango, K.; Valentina, P. Textbook of Medicinal Chemistry, 1st ed; Keerthi Publishers: India, 2007, pp. 327-333.
Ali, A.M.; Ibrahim, A.M.A. Castor and camphor essential oils alter hemocyte populations and induce biochemical changes in larvae of Spodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae). J. Asia Pac. Entomol., 2018, 21(2), 631-637.
Ibrahim, A.M.A.; Thabet, M.A.; Ali, A.M. Physiological and developmental dysfunctions in the dengue vector Culex pipiens (Diptera: Culicidae) immature stages following treatment with zinc oxide nanoparticles. Pestic. Biochem. Physiol., 2023, 192, 105395.
[] [PMID: 37105619]
Finney, D.J. Probit analysis, 3rd ed; Cambridge University Press: Cambridge, UK, 1971.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy