Synthesis, Characterization, Antimicrobial Activity and Anticancer of Some New Pyrazolo[1,5-a]pyrimidines and Pyrazolo[5,1-c]1,2,4-triazines

Author(s): Mona A. Hosny, Yasser H. Zaki*, Wafaa A. Mokbel, Abdou O. Abdelhamid*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020

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Graphical Abstract:


Background: Pyrazole and its derivatives are known to exhibit significant biological and pharmacological activities such as anticancer, anti-inflammatory, antioxidant, antibacterial, analgesic, antiviral, antimicrobial, antifungal, anti-glycemic, antiamoebic, and antidepressive. Considering the immense biological properties, pyrazole is one of the most widely studied nitrogen- containing heterocyclic nuclei. Fused pyrazole derivatives are composed of the pyrazole nucleus attached to other heterocyclic moieties.

Objective: The objective of this article is the synthesis of some new pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c]1,2,4-triazine derivatives with potential anticancer and antimicrobial activities.

Methods: The in vitro growth inhibitory rates (%) and inhibitory growth activity (as measured by IC50) of the newly synthesized compounds were determined against the MCF-7 human breast carcinoma cell line in comparison with the well-known anticancer drug doxorubicin as the standard, using the MTT viability assay. The data generated were used to plot a dose-response curve from which the concentration (μM) of tested compounds required to kill 50% of the cell population (IC50) was determined. Cytotoxic activity was expressed as the mean IC50 of three independent experiments. The difference between inhibitory activities of all compounds with different concentrations was statistically significant p < 0.001. All compounds were structurally characterized by different spectroscopic techniques EI-MS, 1H-NMR, and 13C-NMR, and evaluated for their anticancer and antimicrobial activities (antibacterial and antifungal).

Results: Several pyrazolo[1,5-a]pyrimidine derivatives were synthesized from the reaction of 2-(4- (5-amino-1H-pyrazol-3-yl)phenyl)-1H-indene-1,3(2H)-dione with the appropriate active methylene compounds in boiling ethanol. Also, pyrazolo[5,1-c]triazines were obtained through the reaction of 2-(4-(5-(chlorodiazenyl)-1H-pyrazol-3-yl)phenyl)-1H-indene-1,3(2H)-dione with various active methylene compounds in ethanol containing sodium acetate at 0-5 °C. The structures of the newly synthesized compounds were elucidated on the basis of elemental analysis, spectral data, and alternative synthetic routes whenever possible. The newly synthesized compounds were evaluated for their antitumor activity against a breast cancer cell line (MCF-7) and a human colon cancer cell line (HCT-116). The results revealed that the tested compounds showed high variation in the inhibitory growth rates and activities against the tested tumor cell lines. All newly synthesized compounds screen towards microorganisms e.g. Gram-negative bacteria, Gram-positive bacteria, and Fungi.

Conclusion: 2-(4-(5-Amino-1H-pyrazol-3-yl)phenyl)isoindoline-1,3-dione proved to be a useful precursor for the synthesis of various pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c]-1,2,4- triazines. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses. The newly synthesized compounds were tested in vitro against the MCF-7, HCT-116 human cancer cell line and compared with doxorubicin as the standard, using the MTT viability assay. Most of the tested compounds were found to have moderate to high anticancer activity.

Keywords: Antimicrobial activity, anticancer, anti-inflammatory, antioxidant, antibacterial, Pyrazolo[1, 5-a]pyrimidines, pyrazolo[ 5, 1-c]1, 2, 4-triazines.

Kumar, H.; Saini, D.; Jain, S.; Jain, N. Pyrazole scaffold: a remarkable tool in the development of anticancer agents. Eur. J. Med. Chem., 2013, 70, 248-258.
[] [PMID: 24161702]
Gomha, S.M.; Edrees, M.M.; Faty, R.A.M.; Muhammad, Z.A.; Mabkhot, Y.N. Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents. Chem. Cent. J., 2017, 11(1), 37.
[] [PMID: 29086808]
Aggarwal, R.; Bansal, A.; Rozas, I.; Kelly, B.; Kaushik, P.; Kaushik, D. Synthesis, biological evaluation and molecular modeling study of 5-trifluoromethyl-Δ2-pyrazoline and isomeric 5/3-trifluoromethylpyrazole derivatives as anti-inflammatory agents. Eur. J. Med. Chem., 2013, 70, 350-357.
[] [PMID: 24177361]
Aggarwal, R.; Kumar, S.; Kaushik, P.; Kaushik, D.; Gupta, G.K. Synthesis and pharmacological evaluation of some novel 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles. Eur. J. Med. Chem., 2013, 62, 508-514.
[] [PMID: 23416192]
Mukarram, S.; Bandgar, B.P.; Shaikh, R.U.; Ganapure, S.D.; Chavan, H.V. Synthesis of novel α, α-difluoro-β-hydroxycarbonyl pyrazole derivatives as antioxidant, anti-inflammatory and anticancer agents. Med. Chem. Res., 2017, 26(1), 262-273.
Kumar, V.; Aggarwal, R.; Tyagi, P.; Singh, S.P. Synthesis and antibacterial activity of some new 1-heteroaryl-5-amino-4-phenyl-3-trifluoromethylpyrazoles. Eur. J. Med. Chem., 2005, 40(9), 922-927.
[] [PMID: 15921826]
Aggarwal, R.; Bansal, A.; Rozas, I.; Diez-Cecilia, E.; Kaur, A.; Mahajan, R.; Sharma, J. p-Toluenesulfonic acid-catalyzed solvent free synthesis and biological evaluation of new 1-(4′, 6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives. Med. Chem. Res., 2014, 23(3), 1454-1464.
Aggarwal, R.; Kumar, R.; Kumar, S.; Garg, G.; Mahajan, R.; Sharma, J. Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4, 5-dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-thiocarboxamides and 4-aryl-2-(5 (3)-trifluoromethyl-1-pyrazolyl) thiazoles. J. Fluor. Chem., 2011, 132(11), 965-972.
Saad, H.A.; Osman, N.A.; Moustafa, A.H. Synthesis and analgesic activity of some new pyrazoles and triazoles bearing a 6,8-dibromo-2-methylquinazoline moiety. Molecules, 2011, 16(12), 10187-10201.
[] [PMID: 22157581]
el-Sabbagh, O.I.; Baraka, M.M.; Ibrahim, S.M.; Pannecouque, C.; Andrei, G.; Snoeck, R.; Balzarini, J.; Rashad, A.A. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur. J. Med. Chem., 2009, 44(9), 3746-3753.
[] [PMID: 19419804]
Ouyang, G.; Chen, Z.; Cai, X-J.; Song, B-A.; Bhadury, P.S.; Yang, S.; Jin, L-H.; Xue, W.; Hu, D-Y.; Zeng, S. Synthesis and antiviral activity of novel pyrazole derivatives containing oxime esters group. Bioorg. Med. Chem., 2008, 16(22), 9699-9707.
[] [PMID: 18945621]
Aggarwal, R.; Kumar, V.; Gupta, G.K.; Kumar, V. Synthesis of some new 3, 5-diamino-4-(4′-fluorophenylazo)-1-aryl/heteroaryl pyrazoles as antimicrobial agents. Med. Chem. Res., 2013, 22(8), 3566-3573.
Bekhit, A.A.; Ashour, H.M.; Abdel Ghany, Y.S. Bekhit, Ael-D.; Baraka, A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur. J. Med. Chem., 2008, 43(3), 456-463.
[] [PMID: 17532544]
Bebernitz, G.R.; Argentieri, G.; Battle, B.; Brennan, C.; Balkan, B.; Burkey, B.F.; Eckhardt, M.; Gao, J.; Kapa, P.; Strohschein, R.J.; Schuster, H.F.; Wilson, M.; Xu, D.D. The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice. J. Med. Chem., 2001, 44(16), 2601-2611.
[] [PMID: 11472214]
Yadava, U.; Shukla, B.K.; Roychoudhury, M.; Kumar, D. Pyrazolo[3,4-d]pyrimidines as novel inhibitors of O-acetyl-L-serine sulfhydrylase of Entamoeba histolytica: an in silico study. J. Mol. Model., 2015, 21(4), 96.
[] [PMID: 25799964]
Manikannan, R.; Venkatesan, R.; Muthusubramanian, S.; Yogeeswari, P.; Sriram, D. Pyrazole derivatives from azines of substituted phenacyl aryl/cyclohexyl sulfides and their antimycobacterial activity. Bioorg. Med. Chem. Lett., 2010, 20(23), 6920-6924.
[] [PMID: 20970331]
Özdemir, A.; Altıntop, M.D.; Kaplancıklı, Z.A.; Can, Ö.D.; Demir Özkay, Ü.; Turan-Zitouni, G. Synthesis and evaluation of new 1,5-diaryl-3-[4-(methyl-sulfonyl)phenyl]-4,5-dihydro-1H-pyrazole derivatives as potential antidepressant agents. Molecules, 2015, 20(2), 2668-2684.
[] [PMID: 25658142]
Tominaga, Y.; Honkawa, Y.; Hara, M.; Hosomi, A. Synthesis of pyrazolo [3, 4‐d] pyrimidine derivatives using ketene dithioacetals. J. Heterocycl. Chem., 1990, 27(3), 775-783.
Moukha-chafiq, O.; Taha, M.L.; Lazrek, H.B.; Vasseur, J-J.; Pannecouque, C.; Witvrouw, M.; De Clercq, E. Synthesis and biological activity of some 4-substituted 1-[1-(2,3-dihydroxy-1-propoxy)methyl-1,2,3-triazol-(4 & 5)-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidines. Farmaco, 2002, 57(1), 27-32.
[] [PMID: 11902642]
Boyd, G.V.; Gronowitz, S.; Lowe, P.A. Five-membered ring systems.In:Heterocyclic Chemistry; Suschitzky, H.; Meth-Cohn, O., Eds.; The Royal Society of Chemistry. , 1980, 1, pp. 67-256.
Metzger, J. Comprehensive heterocyclic chemistry. Pergamon Oxford, 1984, 6, 328.
Brown, H. US Pat., 3,278,547, 1966, Chem. Abstr. 1966, p. 18593
Singh, S.; Sehgal, S. Synthesis and phototoxicity of some 2-(phenyl-thienyl-4-substituted or 2-thienyl-4-substituted or 3-thienyl)-4-substituted thiazoles. Indian J. Chem., 1988, 27B, 941-943.
Usui, Y.; Yamano, T. Studies on fungicides. XX. Antifungal activity of 3-aminothiazoline-2-thione and 4H-1,3,4-thiadiazine derivatives. Yakugaku Zasshi, 1969, 89(5), 699-701.
[] [PMID: 5818005]
Goursot, P.; Westrum, E.F., Jr Heat capacity and thermodynamic properties of benzothiazole from 5. deg. to 320. deg. K. J. Chem. Eng. Data, 1969, 14(1), 1-3.
Abdelhamid, A.O.; Abdel-Riheem, N.A.; Emam, H.A. Reactions with hydrazonoyl halides. part XXV. synthesis of some new 2, 3-dihydro-1, 3, 4-thiadiazoles and 5-arylazothiazoles. J. Chem. Res. Synop., 1999, (9), 532-533.
Abdelhamid, A.O.; Elghandour, A.H.; Ahmed, S.A.; Zaki, Y.H. Synthesis and reactions of 2-chloro-2- (hydroximino)-1-(4-methyl-2-phenylthiazol-5-yl)-ethanone. J. Heterocycl. Chem., 2006, 43(2), 249-254.
Abdelhamid, A.O.; Sayed, A.R.; Zaki, Y.H. Reaction of hydrazonoyl halides 511: a facile synthesis of 5-arylthiazoles and triazolino [4, 3-a] pyrimidines as antimicrobial agents. Phosphorus Sulfur Silicon Relat. Elem., 2007, 182(7), 1447-1457.
Abdelhamid, A.O.; Sayed, A.R. Reaction of hydrazonoyl halides 52: Synthesis and antimicrobial activity of some new pyrazolines and 1, 3, 4-thiadiazolines. Phosphorus Sulfur Silicon Relat. Elem., 2007, 182(8), 1767-1777.
Abdelhamid, A.O.; Ismail, Z.H.; El Gendy, M.S.; Ghorab, M.M. Reactions with hydrazonoyl halides 53:1 synthesis and antimicrobial activity of triazolino [4, 3-a] pyrimidines and 5-arylazothiazoles. Phosphorus Sulfur Silicon Relat. Elem., 2008, 182(10), 2409-2418.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
Fu, L.; Feng, X.; Wang, J-J.; Xun, Z.; Hu, J-D.; Zhang, J-J.; Zhao, Y-W.; Huang, Z-B.; Shi, D-Q. Efficient synthesis and evaluation of antitumor activities of novel functionalized 1,8-naphthyridine derivatives. ACS Comb. Sci., 2015, 17(1), 24-31.
[] [PMID: 25412896]
Smania, A., Jr; Monache, F.D.; Smania, E.F.A.; Cuneo, R.S. Antibacterial activity of steroidal compounds isolated from Ganoderma applanatum (Pers.) Pat.(Aphyllophoromycetideae) fruit body. Int. J. Med. Mushrooms, 1999, 1(4), 325-330.
Andrews, J.M. Determination of minimum inhibitory concentrations. J. Antimicrob. Chemother., 2001, 48(suppl- 1), 5-16.
Ahmed, S.A.; Hussein, A.M.; Hozayen, W.G.; El-Ghandour, A.H.; Abdelhamid, A.O. Synthesis of some pyrazolopyrimidines as purine analogues. J. Heterocycl. Chem., 2007, 44(4), 803-810.
Elnagdi, M.H.; Kandeel, E.M.; Elmoghayar, M.R.H. Studies on 3, 5-diamino pyrazoles: chemical behavior of 4-phenylazo-3, 5-diaminopyrazoles. Z. Naturforsch. B, 1977, 32(3), 307-310.

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Article Details

Year: 2020
Published on: 06 September, 2020
Page: [750 - 760]
Pages: 11
DOI: 10.2174/1573406415666190620144404
Price: $65

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