A Review on Synthesis and Pharmacological Activity of Coumarins and Their Analogs

Author(s): Moustafa A. Gouda*, Mohammed A. Salem, Mohamed H. Helal

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 6 , 2020

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Graphical Abstract:


Background: Coumarins were reported to possess antimicrobial, antiinflammatory, antiplasmodial, antimalarial, and enzyme inhibitory properties. Furthermore, coumarins are a type of vitamin K antagonists. Coumarins had been first organized through perkin reaction; besides Knoevenagel condensation was mentioned as a critical synthetic approach for the synthesis of 3-substituted coumarins. Moreover, Pechmann, Reformatasky and Witting reactions were stated for the preparation of coumarins.

Methods: We undertook a structured search of the method of preparation, the chemical reactivity and biological properties that are associated with coumarins and their analogous.

Results: Coumarins display a wide range of Src Kinase and cholinesterase inhibitor activities and application of coumarins as antidiabetic, antipsychotic and antiproliferative agents has been addressed. Other properties of coumarins such as their role in antitumor, anticancer, and as antioxidants have also been reviewed.

Conclusion: This review concluded that coumarin ring was mixed with other rings, a synergistic effect for each of the ring in their biological activities was obtained, such compounds were exploited to improve various important molecules which provide scaffolds for drug improvement. These compounds were used to broaden a special molecule that gives scaffolds for drug improvement.

Keywords: Coumarins, Pechmann, Knoevenagel, synthesis, biological activity, anti-inflammatory.

Zaffer, A.M.; Ali, M.; Mir, R.S. New sesqui and diterpenic coumarin ethers from the roots of Aegle marmelos (L.). Corr. Nat. Prod. J., 2012, 2(4), 252-258.
Ashok, D.; Lakshmi, V.B.; Sarasija, M. An Efficient Micro-wave-Assisted Suzuki cross-coupling on coumarin derivatives in water and evaluation of antimicrobial activity. Lett. Org. Chem., 2016, 13(1), 76-84.
Chaudhari, K.H.A.; Siddikia, A.D.; Manohara, Y. Design and synthesis of novel oxadiazole and diphenyl ether hydrazone derivatives of coumarin as potential antibacterial agents. Curr. Bioact. Compd., 2017, 13(4), 318-325.
Hadjipavlou-Litina, D.J.; Litinas, K.E.; Kontogiorgis, C. The anti-inflammatory effect of coumarin and its derivatives. Antiinflamm. Antiallergy Agents Med. Chem., 2007, 6(4), 293-306.
Thomas, V.; Giles, D.; Basavarajaswamy, P.M.A. Coumarin derivatives as anti-inflammatory and anticancer agents Anti-Cancer Agent. Me., 2017, 17(3), 415-423.
Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E.; Nicolaides, D.N. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Curr. Pharm. Des., 2004, 10(30), 3813-3833.
[http://dx.doi.org/10.2174/1381612043382710] [PMID: 15579073]
Bubols, G.B. Vianna, Dda.R.; Medina-Remon, A.; von Poser, G.; Lamuela-Raventos, R.M.; Eifler-Lima, V.L.; Garcia, S.C. The antioxidant activity of coumarins and flavonoids. Mini Rev. Med. Chem., 2013, 13(3), 318-334.
[PMID: 22876957]
Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: A promising scaffold for anticancer agents Anti-Cancer Agent. Me., 2015, 15(8), 1032-1048.
Bouhenna, M.M.; Mameri, N.; Pérez, M.V.; Talhi, O.; Bacha-ri, K.; Silva, A.; Luyten, W. Anticancer activity study of chromone and coumarin hybrids using electrical impedance spectroscopy. Anti-Cancer Agent., 2018, 18(6), 854-864.
Jamier, V.; Marut, W.; Valente, S.; Chéreau, C.; Chouzenoux, S.; Nicco, C.; Lemaréchal, H.; Weill, B.; Kirsch, G.; Jacob, C.; Batteux, F. Chalcone-Coumarin derivatives as potential anti-cancer drugs: An in vitro and in vivo investigation Anti-Cancer Agent. Me, 2014, 14(7), 963-974.
Musa, M.A.; Zhou, A.; Sadik, O.A. Synthesis and antiproliferative activity of new coumarin-based benzopyranone derivatives against human tumor cell lines. Med. Chem., 2011, 7(2), 112-120.
[http://dx.doi.org/10.2174/157340611794859280] [PMID: 21222615]
Hu, X.L.; Gao, C.; Xu, Z.; Liu, M.L.; Feng, L.S.; Zhang, G.D. Recent development of coumarin derivatives as potential antiplasmodial and antimalarial agents. Curr. Top. Med. Chem., 2018, 18(2), 114-123.
[http://dx.doi.org/10.2174/1568026618666171215101158] [PMID: 29243579]
Kamal, A.; Satyanarayana, M.; Devaiah, V.; Rohini, V.; Yadav, J.S.; Mullick, B.; Nagaraja, V. Synthesis and biological evaluation of coumarin linked fluoroquinolones, phthalimides and naphthalimides as potential DNA gyrase inhibitors. Lett. Drug Des. Discov., 2006, 3(7), 494-502.
Wadhwa, P.; Jain, P.; Rudrawar, S.; Jadhav, H.R.A. Quinoline, coumarin and other heterocyclic analogs based HIV-1 integrase inhibitors. Curr. Drug Discov. Technol., 2018, 15(1), 2-19.
[http://dx.doi.org/10.2174/1570163814666170531115452] [PMID: 28558629]
Wang, C.; Xu, F.; Niu, Y.; Wu, Y.; Sun, J.; Peng, Y.; Liang, L.; Xu, P. Synthesis and biological evaluations of 3-benzothiazol-2-yl coumarin derivatives as MEK1 inhibitors. Lett. Drug Des. Discov., 2013, 10(8), 727-732.
Schalekamp, T.; de Boer, A. Pharmacogenetics of oral anticoagulant therapy. Curr. Pharm. Des., 2010, 16(2), 187-203.
[http://dx.doi.org/10.2174/138161210790112737] [PMID: 20205664]
Shaabani, A.; Ghadari, R.; Rahmati, A.; Rezayan, A.H. Cou-marin synthesis via Knoevenagel condensation reaction in 1, 1, 3, 3-N, N, N′, N′-tetramethylguanidinium trifluoroacetate ionic liquid. J. Iran. Chem. Soc., 2009, 6(4), 710-714. [JICS]
Zambare, S. Recent advances in the synthesis of coumarin derivatives via Pechmann condensation. Curr. Org. Chem., 2016, 20(7), 798-828.
Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P.K.; Mamledesai, S.; Thippeswamy, A.H.M.; Satyanarayana, D. Synthesis and pharmacological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2009, 44(4), 1682-1688.
[http://dx.doi.org/10.1016/j.ejmech.2008.09.020] [PMID: 18986738]
Osman, H.; Arshad, A.; Lam, C.K.; Bagley, M.C. Microwave-assisted synthesis and antioxidant properties of hydrazinyl thiazolyl coumarin derivatives. Chem. Cent. J., 2012, 6(1), 32-32.
[http://dx.doi.org/10.1186/1752-153X-6-32] [PMID: 22510146]
Kurt, B.Z.; Gazioglu, I.; Sonmez, F.; Kucukislamoglu, M. Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives. Bioorg. Chem., 2015, 59, 80-90.
[http://dx.doi.org/10.1016/j.bioorg.2015.02.002] [PMID: 25706320]
Gouda, M.A.; Berghot, M.A.; Baz, E.A.; Hamama, W.S. Synthesis, antitumor and antioxidant evaluation of some new thiazole and thiophene derivatives incorporated coumarin moiety. Med. Chem. Res., 2012, 21, 1062-1070.
Karrer, K.; Rubini, J.R. On the fate of labelled Ehrlich ascites cells in mice, an autoradiographic study using H3 thymidine. Med. Pharmacol. Exp. Int. J. Exp. Med., 1965, 13(2), 124-130.
[PMID: 5897045]
Pechmann, H.V.; Duisberg, C. Above the compounds of phenols with acetate gases. Ber. Dtsch. Chem. Ges., 1883, 16, 2119.
Al-Ayed, A.S. Synthesis, spectroscopy and electrochemistry of new 3-(5-Aryl-4, 5-Dihydro-1H-Pyrazol-3-yl)-4-Hydroxy-2H-Chromene-2-One 4, 5 as a novel class of po-tential antibacterial and antioxidant derivatives. Int. J. Org. Chem. (Irvine), 2011, 1, 87-96. [IJOC]
Manojkumar, P.; Ravi, T.K.; Subbuchettiar, G. Synthesis of coumarin heterocyclic derivatives with antioxidant activity and in vitro cytotoxic activity against tumour cells. Acta Pharm., 2009, 59(2), 159-170.
[http://dx.doi.org/10.2478/v10007-009-0018-7] [PMID: 19564141]
Hafez, O.M.; Nassar, M.I.; El-Kousy, S.M.; Abdel-Razik, A.F.; Sherien, M.M.; El-Ghonemy, M.M. Synthesis of some new carbonitriles and pyrazole coumarin derivatives with potent antitumor and antimicrobial activities. Acta Pol. Pharm., 2014, 71(4), 594-601.
[PMID: 25272885]
Gabr, M.T.; El-Gohary, N.S.; El-Bendary, E.R.; El-Kerdawy, M.M.; Ni, N. Microwave-assisted synthesis and antitumor evaluation of a new series of thiazolylcoumarin derivatives. EXCLI J., 2017, 16, 1114-1131.
[PMID: 29285008]
Dawoud, N.T.A.; Abdel-Ghaffar, N.F.; Soliman, F.M.A.; Abdl-galil, M.M.; Zaki, H.M. Synthesis, characterization and anti-cancer activity of some new heterocycles bearing coumarin moiety. Arch. Nat. Med. Chem., 2017, 2017, 1-10.
El‐Naggar, A.M.; Hemdan, M.M.; Atta‐Allah, S.R. An Effi-cient One‐Pot Synthesis of new coumarin derivatives as potent anticancer agents under microwave irradiation. J. Heterocycl. Chem., 2017, 54, 3519-3526.
Mohareb, R.M. MegallyAbdo, N.Y. Uses of 3-(2-Bromoacetyl)-2H-chromen-2-one in the Synthesis of heterocyclic compounds incorporating coumarin: Synthesis, characterization and cytotoxicity. Molecules, 2015, 20(6), 11535-11553.
[http://dx.doi.org/10.3390/molecules200611535] [PMID: 26111181]
Kathuria, A.; Jalal, S.; Tiwari, R.; Shirazi, A.N.; Gupta, S.; Kumar, S.; Parang, K.; Sharma, S.K. Substituted coumarin derivatives: Synthesis and evaluation of antiproliferative and Src kinase inhibitory activities. Chem. Biol. Interact., 2011, 1, 279-296.
Maggi, R.; Bigi, F.; Carloni, S.; Mazzacani, A.; Sartori, G. Uncatalysed reactions in water: Part 2. Preparation of 3‐carboxycoumarins. Green Chem., 2011, 3, 173-174.
Song, A.; Wang, X.; Lam, K.S. A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum’s acid with ortho-hydroxyaryl aldehydes or ke-tones. Tetrahedron Lett., 2003, 44, 1755-1758.
Arora, P.; Das, S.; Ranawat, M.S.; Arora, N.; Gupta, M.M. Synthesis and biological evaluation of some novel chromene-2-one derivatives for antipsychotic activity. J. Chem. Pharm. Res., 2010, 2, 317-323.
Torres, F.C.; Gonçalves, G.A.; Vanzolini, K.L.; Merlo, A.A.; Gauer, B.; Holzschuh, M.; Andrade, S.; Piedade, M.; Garcia, S.C.; Carvalho, I.; Poser, G.L.V.; Kawano, D.F.; Eifler-Lima, V.L.; Cassc, Q.B. Combining the pharmacophore features of coumarins and 1,4-substituted 1,2,3-triazoles to design new acetylcholinesterase inhibitors: fast and easy generation of 4-Methylcoumarins/1,2,3-triazoles conjugates via click chemistry. J. Braz. Chem. Soc., 2016, 27, 1541-1550.
Gulcan, H.O.; Unlu, S.; Esiringu, I.; Ercetin, T.; Sahin, Y.; Oz, D.; Sahin, M.F. Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors. Bioorg. Med. Chem., 2014, 22(19), 5141-5154.
[http://dx.doi.org/10.1016/j.bmc.2014.08.016] [PMID: 25189690]
Farina, R.; Pisani, L.; Catto, M.; Nicolotti, O.; Gadaleta, D.; Denora, N.; Soto-Otero, R.; Mendez-Alvarez, E.; Passos, C.S.; Muncipinto, G.; Altomare, C.D.; Nurisso, A.; Carrupt, P.A.; Carotti, A. Structure-based design and optimization of multitarget-directed 2 H-chromen-2-one derivatives as potent inhibitors of monoamine oxidase B and cholinesterases. J. Med. Chem., 2015, 58(14), 5561-5578.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00599] [PMID: 26107513]
Prajapati, V.G.; Sen, D.J. Synthesis and biological evaluation of some novel coumarin and guanidine derivatives by oral glucose tolerance test. Am. J. Adv. Drug Deliv., 2013, 2, 141-148.

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Year: 2020
Published on: 01 October, 2020
Page: [818 - 836]
Pages: 19
DOI: 10.2174/1573407215666190405154406
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