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Current Organic Synthesis

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ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Research Article

Design, Synthesis and Biological Evaluation of Cyanopyridines, Pyridopyrazolopyrimidines and Pyridopyrazolotriazines as Potential Anticancer Agents

Author(s): Reda Mohammed Keshk* and Batoul Mohamed Izzularab

Volume 18, Issue 5, 2021

Published on: 29 December, 2020

Page: [483 - 492] Pages: 10

DOI: 10.2174/1570179417666201229163045

Price: $65

Abstract

Background: The continuous need for new anticancer drugs is never-ending task due to cancer resistance to the existing drugs.

Objective: This article aimed to design, synthesis, characterization, and anticancer evaluation of cyanopyridines, pyridopyrazolopyrimidines and pyridopyrazolotriazines.

Methods: Anticancer activity of the synthesized compounds was determined using MTT assay against three cancer cell lines, namely liver cancer cell line (HepG-2), pancreatic cancer cell line (PANC-1), non-small lung cancer cell line (A-549) and normal fibroblast.

Results and Discussion: A series of 3-cyanopyridines (2a,b, 4, 5, 9), pyridopyrimidine (10), pyridopyrazolopyrimidines (11a-c, 12a,b, 18), pyrazolopyridine salt (13) and pyridopyrazolotriazines (16a,b) were synthesized from 3-cyano-4,6-dimethyl-2-pyridone. The synthesized compounds were evaluated in vitro for their anticancer activity and their chemical structures were determined by elemental analysis and spectroscopic data.

Conclusion: Some of the synthesized compounds showed remarkable anticancer activities, especially 11a exhibited superior potency to the reference drug cisplatin against A-549 (IC50 = 9.24 μg mL-1 compared to 11.76 μg mL-1 for reference drug) and was found to be safe (IC50 = 66 μg mL-1) for normal fibroblast. Furthermore, compound 16a displayed the highest activity among the tested compounds against HepG-2 (IC50 = 6.45 μg mL-1 equipotent to cisplatin) with the highest safety profile for normal fibroblast (IC50=113.97 μg mL-1).

Keywords: Cyanopyridines, pyrazolopyridines, pyrazolopyridine salt, pyridopyrazolopyrimidines, pyridopyrazolotriazines, anticancer activity, cytotoxicity assay.

Graphical Abstract

[1]
Haoran, W.; Akhtar, W.; Nainwal, L.M.; Kaushik, S.K.; Akhter, M.; Shaquiquzzaman, M.; Alam, M.M. Synthesis and biological evaluation of benzimidazole pendant cyanopyrimidine derivatives as anticancer agents. J. Heterocycl. Chem., 2020, 57, 3350-3360.
[http://dx.doi.org/10.1002/jhet.4052]
[2]
Akhtar, W.; Nainwal, L.M.; Kaushik, S.K.; Akhtar, M.; Shaquiquzzaman, M.; Almalki, F.; Saifullah, K.; Marella, A.; Alam, M.M. Methylene-bearing sulfur-containing cyanopyrimidine derivatives for treatment of cancer: Part-II. Arch. Pharm. (Weinheim), 2020, 353(5)e1900333
[http://dx.doi.org/10.1002/ardp.201900333] [PMID: 32115728]
[3]
Abdel-Aziz, H.M.; Gomha, S.M.; El-Sayed, A.A.; Mabkhot, Y.N.; Alsayari, A.; Muhsinah, A.B. Facile synthesis and antiproliferative activity of new 3-cyanopyridines. BMC Chem, 2019, 13(1), 137.
[http://dx.doi.org/10.1186/s13065-019-0652-1] [PMID: 31891163]
[4]
Sabour, R.; Harras, M.F.; Mohamed Al Kamaly, O.; Altwaijry, N. Discovery of novel 3-cyanopyridines as survivin modulators and apoptosis inducers. Molecules, 2020, 25(21), 4892.
[http://dx.doi.org/10.3390/molecules25214892] [PMID: 33105831]
[5]
Abbas, I.; Gomha, S.; Elasser, M.; Bauomi, M. Synthesis and biological evaluation of new pyridines containing imidazole moiety as antimicrobial and anticancer agents. Turk. J. Chem., 2015, 39, 334-346.
[http://dx.doi.org/10.3906/kim-1410-25]
[6]
Abadi, A.H.; Ibrahim, T.M.; Abouzid, K.M.; Lehmann, J.; Tinsley, H.N.; Gary, B.D.; Piazza, G.A. Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors. Bioorg. Med. Chem., 2009, 17(16), 5974-5982.
[http://dx.doi.org/10.1016/j.bmc.2009.06.063] [PMID: 19628397]
[7]
Hassan, A.Y.; Sarg, M.T.; El-Sebaey, S.A. Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3‐b]pyridine: Part 2. J. Heterocycl. Chem., 2020, 57, 694-715.
[http://dx.doi.org/10.1002/jhet.3810]
[8]
Ahmed, M.H.; El-Hashash, M.A.; Marzouk, M.I.; El-Naggar, A.M. Design, synthesis, and biological evaluation of novel pyrazole, oxazole, and pyridine derivatives as potential anticancer agents using mixed chalcone. J. Heterocycl. Chem., 2019, 56, 114-123.
[http://dx.doi.org/10.1002/jhet.3380]
[9]
Sofan, M.A.; Hamama, W.S. EL-Hawary, I. I.; Ibrahim, I. T.; Zoorob, H. H.; Synthesis, labeling and biological evalution of new thiopyrano[2,3-b]pyridine derivatives as potential anticancer agents. Acta Chim. Slov., 2019, 66, 592-602.
[http://dx.doi.org/10.17344/acsi.2019.4980]
[10]
Amr, A.E.; Abdalla, M.M. Anticancer activities of some synthesized 2,4,6-trisubstituted pyridine candidates. Biomed. Res., 2016, 27(3), 731-736.
[11]
Elansary, A.K.; Moneer, A.A.; Kadry, H.H.; Gedawy, E.M. Synthesis and anticancer activity of some novel fused pyridine ring system. Arch. Pharm. Res., 2012, 35(11), 1909-1917.
[http://dx.doi.org/10.1007/s12272-012-1107-6] [PMID: 23212632]
[12]
Nicolaou, K.C.; Scarpelli, R.; Bollbuck, B.; Werschkun, B.; Pereira, M.M.; Wartmann, M.; Altmann, K.H.; Zaharevitz, D.; Gussio, R.; Giannakakou, P. Chemical synthesis and biological properties of pyridine epothilones. Chem. Biol., 2000, 7(8), 593-599.
[http://dx.doi.org/10.1016/S1074-5521(00)00006-5] [PMID: 11048950]
[13]
Badr, M.H.; Rostom, S.A.F.; Radwan, M.F. Novel polyfunctional pyridines as anticancer and antioxidant agents. Synthesis, biological evaluation and in silico ADME-T study. Chem. Pharm. Bull. (Tokyo), 2017, 65(5), 442-454.
[http://dx.doi.org/10.1248/cpb.c16-00761] [PMID: 28458366]
[14]
Fekry, R.M. EL-sayed, H. A.; Assy, M. G.; Shalby, A.; Mohamed, A. S., Synthesis and anticancer activity of some novel fused nicotinonitrile derivatives. Organic Chem. Curr. Res., 2016, 5(4), 1-4.
[http://dx.doi.org/10.4172/2161-0401.1000171]
[15]
Kotb, E.R.; El-Hashash, M.A.; Salama, M.A.; Kalf, H.S. Abdel wahed, N. A., Synthesis and reactions of some novel nicotinonitrile derivatives for anticancer and antimicrobial evaluation. Acta Chim. Slov., 2009, 56, 908-919.
[16]
Mohamed, M.S.; Awad, Y.E.; El-Hallouty, S.M.; El-Araby, M. Design, synthesis and cancer cell line activities of pyrazolo[3,4-b]pyridine derivatives. Open J. Med. Chem., 2012, 2, 78-88.
[http://dx.doi.org/10.4236/ojmc.2012.23010]
[17]
Waly, M.A. EL-Hawary, I. I.; Hamama, W. S.; Zoorob, H. H., Synthesis and antitumor evaluation of some new fused and binary pyridines. J. Heterocycl. Chem., 2013, 50, 12-17.
[http://dx.doi.org/10.1002/jhet.1020]
[18]
Elsaedany, S.K.; Zein, M.A. AbedelRehim, E. M.; Keshk, R. M., Synthesis, antimicrobial, and cytotoxic activities evaluation of some new pyrido[2,3-d]pyrimidines. J. Heterocycl. Chem., 2016, 53, 1534-1543.
[http://dx.doi.org/10.1002/jhet.2460]
[19]
Baldwin, J.J.; Engelhardt, E.L.; Hirschmann, R.; Ponticello, G.S.; Atkinson, J.G.; Wasson, B.K.; Sweet, C.S.; Scriabine, A. Heterocyclic analogues of the antihypertensive beta-adrenergic blocking agent (S)-2-[3-(ter-butylamino)-2-hydroxypropoxy]-3-cyanopyridine. J. Med. Chem., 1980, 23(1), 65-70.
[http://dx.doi.org/10.1021/jm00175a012] [PMID: 6102151]
[20]
Manna, F.; Chimenti, F.; Bolasco, A.; Filippelli, A.; Palla, A.; Filippelli, W.; Lampa, E.; Mercantini, R. Anti-inflammatory, analgesic and antipyretic 4,6-disubstituted 3-cyanopyridine-2-ones and 3-cyano-2-aminopyridines. Eur. J. Med. Chem., 1992, 27, 627-632.
[21]
Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Masuda, T.; Shintani, T.; Sato, H.; Koriyama, Y.; Fukushima, K.; Nunami, N.; Yamauchi, M.; Fuchikami, K.; Komura, H.; Watanabe, A.; Ziegelbauer, K.B.; Bacon, K.B.; Lowinger, T.B. Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg. Med. Chem. Lett., 2004, 14(15), 4019-4022.
[http://dx.doi.org/10.1016/j.bmcl.2004.05.041] [PMID: 15225718]
[22]
Hamdy, N.A.; Gamal-Eldeen, A.M. New pyridone, thioxopyridine, pyrazolopyridine and pyridine derivatives that modulate inflammatory mediators in stimulated RAW 264.7 murine macrophage. Eur. J. Med. Chem., 2009, 44(11), 4547-4556.
[http://dx.doi.org/10.1016/j.ejmech.2009.06.023] [PMID: 19616348]
[23]
Lahsasni, S.A.; Al Korbi, F.H.; Aljaber, N.A.A. Synthesis, characterization and evaluation of antioxidant activities of some novel chalcones analogues. Chem. Cent. J., 2014, 8(32), 1-10.http://journal.chemistrycentral.com/content/8/1/32
[http://dx.doi.org/10.1186/1752-153X-8-32]
[24]
Sayed, H.H.; Morsy, E.M.; Flefel, E.M. Synthesis and reactions of some novel nicotinonitrile, thiazolotriazole, and imidazolotriazole derivatives for antioxidant evaluation. Synth. Commun., 2010, 40, 1360-1370.
[http://dx.doi.org/10.1080/00397910903079631]
[25]
Gouda, M.A.; Helal, M.H. Synthesis and antioxidant evaluation of some new pyridines. Eur. J. Chem., 2015, 6, 84-87.
[http://dx.doi.org/10.5155/eurjchem.6.1.84-87.1149]
[26]
Gouda, M.A.; Berghot, M.A.; Abd El-Ghani, G.E.; Khalil, A. Synthesis and antioxidant evaluation of some nicotinonitriles. J. Heterocycl. Chem., 2016, 53, 1241-1250.
[http://dx.doi.org/10.1002/jhet.2414]
[27]
Maqbool, M.; Manral, A.; Jameel, E.; Kumar, J.; Saini, V.; Shandilya, A.; Tiwari, M.; Hoda, N.; Jayaram, B. Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents. Bioorg. Med. Chem., 2016, 24(12), 2777-2788.
[http://dx.doi.org/10.1016/j.bmc.2016.04.041] [PMID: 27157006]
[28]
Haghighijoo, Z.; Akrami, S.; Saeedi, M.; Zonouzi, A.; Iraji, A.; Larijani, B.; Fakherzadeh, H.; Sharifi, F.; Arzaghi, S.M.; Mahdavi, M.; Edraki, N. N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer’s disease. Bioorg. Chem., 2020, 103104146
[http://dx.doi.org/10.1016/j.bioorg.2020.104146] [PMID: 32777579]
[29]
Zhu, Z.; Yang, T.; Zhang, L.; Liu, L.; Yin, E.; Zhang, C.; Guo, Z.; Xu, C.; Wang, X. Inhibiting Aβ toxicity in Alzheimer’s disease by a pyridine amine derivative. Eur. J. Med. Chem., 2019, 168, 330-339.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.052] [PMID: 30826509]
[30]
Kumar, J.; Gill, A.; Shaikh, M.; Singh, A.; Shandilya, A.; Jameel, E.; Sharma, N.; Mrinal, N.; Hoda, N.; Jayaram, B. Pyrimidine-triazolopyrimidine and pyrimidine-pyridine hybrids as potential acetylcholinesterase inhibitors for alzheimer’s disease. Med. Chem. Drug Discovery, 2018, 3, 736-747.
[http://dx.doi.org/10.1002/slct.201702599]
[31]
Kaminski, K.; Obniska, J.; Zagorska, A.; Maciag, D. Synthesis, physicochemical and anticonvulsant properties of new N-(pyridine-2-yl) derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part II. Arch. Pharm. (Weinheim), 2006, 339(5), 255-261.
[http://dx.doi.org/10.1002/ardp.200500219] [PMID: 16511896]
[32]
Amr, Ael-G.; Sayed, H.H.; Abdulla, M.M. Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents. Arch. Pharm. (Weinheim), 2005, 338(9), 433-440.
[http://dx.doi.org/10.1002/ardp.200500982] [PMID: 16134091]
[33]
Tripathi, L.; Singh, R.; Stables, J.P. Design & synthesis of N′-[substituted] pyridine-4-carbohydrazides as potential anticonvulsant agents. Eur. J. Med. Chem., 2011, 46(2), 509-518.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.030] [PMID: 21167624]
[34]
Wang, S.; Liu, H.; Wang, X.; Lei, K.; Li, G.; Li, X.; Wei, L.; Quan, Z. Synthesis and evaluation of anticonvulsant activities of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-b ]pyridine derivatives. Arch. Pharm. (Weinheim), 2019, 352(10)e1900106
[http://dx.doi.org/10.1002/ardp.201900106] [PMID: 31364202]
[35]
Amr, A.E.; Al-Omar, M.A.; Abdalla, M.M. Analgesic, anticonvulsant and antiparkinsonian activities of some synthesized 2,6-bis(Tetracarboxamide)-pyridine and macrocyclic tripeptide derivatives. Int. J. Pharmacol., 2016, 12(2), 74-80.
[http://dx.doi.org/10.3923/ijp.2016.74.80]
[36]
Guan, L.P.; Zhang, R.P.; Sun, Y.; Chang, Y.; Sui, X. Synthesis and studies on the anticonvulsant activity of 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives. Arzneimittelforschung, 2012, 62(8), 372-377.
[http://dx.doi.org/10.1055/s-0032-1314821] [PMID: 22782505]
[37]
Siddiqui, N.; Ahsan, W.; Alam, M.S.; Ali, R.; Srivastava, K.; Ahmed, S. Anticonvulsant activity of a combined pharmacophore of pyrazolo-pyridines with lesser toxicity in mice. Bull. Korean Chem. Soc., 2011, 32, 576-582.
[http://dx.doi.org/10.5012/bkcs.2011.32.2.576]
[38]
Cheney, I.W.; Yan, S.; Appleby, T.; Walker, H.; Vo, T.; Yao, N.; Hamatake, R.; Hong, Z.; Wu, J.Z. Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase. Bioorg. Med. Chem. Lett., 2007, 17(6), 1679-1683.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.086] [PMID: 17251021]
[39]
Wendt, M.D.; Sun, C.; Kunzer, A.; Sauer, D.; Sarris, K.; Hoff, E.; Yu, L.; Nettesheim, D.G.; Chen, J.; Jin, S.; Comess, K.M.; Fan, Y.; Anderson, S.N.; Isaac, B.; Olejniczak, E.T.; Hajduk, P.J.; Rosenberg, S.H.; Elmore, S.W. Discovery of a novel small molecule binding site of human survivin. Bioorg. Med. Chem. Lett., 2007, 17(11), 3122-3129.
[http://dx.doi.org/10.1016/j.bmcl.2007.03.042] [PMID: 17391963]
[40]
Aqui, N.A.; Vonderheide, R.H. Survivin as a universal tumor antigen for novel cancer immunotherapy: functions of a killer clone. Cancer Biol. Ther., 2008, 7(12), 1888-1889.
[http://dx.doi.org/10.4161/cbt.7.12.7219] [PMID: 19158476]
[41]
Ambrosini, G.; Adida, C.; Altieri, D.C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med., 1997, 3(8), 917-921.
[http://dx.doi.org/10.1038/nm0897-917] [PMID: 9256286]
[42]
Soh, J.W.; Mao, Y.; Kim, M.G.; Pamukcu, R.; Li, H.; Piazza, G.A.; Thompson, W.J.; Weinstein, I.B. Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin. Cancer Res., 2000, 6(10), 4136-4141.
[PMID: 11051267]
[43]
Cheng, J.; Grande, J.P. Cyclic nucleotide phosphodiesterase (PDE) inhibitors: novel therapeutic agents for progressive renal disease. Exp. Biol. Med. (Maywood), 2007, 232(1), 38-51.
[PMID: 17202584]
[44]
Yassin, F.A. Synthesis, reactions and biological activity of 2-substituted 3-cyano-4,6-dimethylpyridine derivatives. Chem. Heterocyclic Chem., 2009, 45(1), 35-41.
[45]
Zonouzi, A.; Izakian, Z.; Ng, S.W. Novel synthesis of some new fluorescent 2-amino-3-cyanopyridines. Heterocycles, 2012, 85(11), 2713-2721.
[http://dx.doi.org/10.3987/COM-12-12566]
[46]
Keshk, R.M.; Garavelli, M.; El-tahawy, M.M. Synthesis, physicochemical and vibrational spectral properties of 2–pyridone and 2–aminopyridine derivatives: An experimental and theoretical study. J. Mol. Struct., 2021, 1225(5)
[http://dx.doi.org/10.1016/j.molstruc.2020.129136]
[47]
Keshk, R.M. Design and synthesis of new series of 3-cyanopyridine and pyrazolopyridine derivatives. J. Heterocyclic Chem, 2020, 1-10.
[48]
Mitry, R.R.; Hughes, R.D.; Bansal, S.; Lehec, S.C.; Wendon, J.A.; Dhawan, A. Effects of serum from patients with acute liver failure due to paracetamol overdose on human hepatocytes in vitro. Transplant. Proc., 2005, 37(5), 2391-2394.
[http://dx.doi.org/10.1016/j.transproceed.2005.03.019] [PMID: 15964424]
[49]
Elassar, A.Z.A. Synthesis and reactions of 3-cyano-4,6-dimethyl-2-pyridone. J. Heterocycl. Chem., 2011, 48, 272-278.
[http://dx.doi.org/10.1002/jhet.545]
[50]
Buján, E.I.; Cañas, A.I.; Rossi, R.H. Amines as leaving groups in nucleophilic aromatic substitution reactions. Part 5.1 Substitution vs. N-oxide formation in the reaction of N-n-butyl-2,6-dinitroaniline with hydroxide ions. J. Chem. Soc., Perkin Trans. 2, 2001, 1973-1977.
[51]
Wiberg, K.B.; Wang, Y.G.; Miller, S.J.; Puchlopek, A.L.A.; Bailey, W.F.; Fair, J.D. Disparate behavior of carbonyl and thiocarbonyl compounds: acyl chlorides vs thiocarbonyl chlorides and isocyanates vs isothiocyanates. J. Org. Chem., 2009, 74(10), 3659-3664.
[http://dx.doi.org/10.1021/jo9004316] [PMID: 19371054]
[52]
Wiberg, K.B.; Wang, Y. A comparison of some properties of C=O and C=S bonds. ARKIVOC, 2011, (5), 45-56.
[http://dx.doi.org/10.3998/ark.5550190.0012.506]

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