Synthesis of 2-Substituted 4-Arylidene-5(4H)-oxazolones as Potential Cytotoxic Agents in the Presence of Lemon Juice as a Biocatalyst

Author(s): Malavattu G. Prasad, Chapala V. Lakshmi, Naresh K. Katari*, Krishnan Anand, Manojit Pal*, Sreekantha B. Jonnalagadda

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 22 , Issue 9 , 2019

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Abstract:

Background: The oxazolone class of compounds is known to exert a profound effect on malignant cell proliferation, tumor angiogenesis and /or on the established neoplastic vasculature. Additionally, these compounds are generally known to have a low tendency to interact with DNA which is not common with most of the conventional cytotoxic agents. Thus, this class of compounds is of particular interest for the discovery and development of patient-friendly anticancer agents.

Objective: The initial objective of this study was to synthesize and evaluate 2-substituted 4-arylidene- 5(4H)-oxazolones for their potential anticancer properties.

Methods: A simple, mild and non-hazardous synthetic methodology has been developed for the preparation of 2-substituted 4-arylidene-5(4H)-oxazolones. The methodology involved lemon juice mediated condensation of N-acyl glycine derivatives including hippuric acid with arylaldehydes in PEG-400 under ultrasound irradiation. All the synthesized compounds were screened via an MTT assay for their potential cytotoxic properties in vitro using the cancerous cell lines e.g. K562 (human chronic myeloid leukemia), Colo-205 (human colon carcinoma), and A549 (human lung carcinoma) and a non-cancerous HEK293 (human embryonic kidney) cell line.

Results: Compounds 3a, 3c and 3i showed promising growth inhibition against A549 cell line but no significant effects on HEK293 cell line, indicating their selectivity towards cancer cells. Moreover, their IC50 values suggested that all these compounds were comparable to the reference drug doxorubicin indicating their potential against lung cancer.

Conclusion: The 4-arylidene-5(4H)-oxazolone framework presented here could be a new template for the design and discovery of potential anticancer agents especially for lung cancer.

Keywords: Lemon juice, ultrasound, 4-arylidene-5(4H)-oxazolone derivatives, anticancer, drug doxorubicin, lung cancer.

[1]
Erlenmeyer, E. Ueber die Condensation der Hippursäure mit Phtalsäureanhydrid und mit Benzaldehyd. Annalen, 1893, 275, 1-8.
[http://dx.doi.org/10.1002/jlac.18932750102]
[2]
Sharma, N.; Banerjee, J.; Shrestha, N.; Chaudhury, D. A review on oxazolone, it’s method of synthesis and biological activity. Eur. J. Biomed. Pharm. Sci., 2015, 2, 964-987.
[3]
Argade, N.D.; Kalrale, B.K.; Gill, C.H. microwave assisted improved method for the synthesis of pyrazole containing 2,4,-disubstitutedoxazole-5-one and their antimicrobial activity. Eur. J. Chem., 2008, 5, 120-129.
[4]
Tandon, M.; Coffen, D.L.; Gallant, P.; Keith, D.; Ashwell, M.A. Potent and selective inhibitors of bacterial methionyl tRNA synthetase derived from an oxazolone-dipeptide scaffold. Bioorg. Med. Chem. Lett., 2004, 14(8), 1909-1911.
[http://dx.doi.org/10.1016/j.bmcl.2004.01.094] [PMID: 15050625]
[5]
Parveen, M.; Ali, A.; Ahmed, S.; Malla, A.M.; Alam, M.; Pereira Silva, P.S.; Silva, M.R.; Lee, D.U. Synthesis, bioassay, crystal structure and ab initio studies of Erlenmeyer azlactones. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2013, 104, 538-545.
[http://dx.doi.org/10.1016/j.saa.2012.11.054] [PMID: 23314102]
[6]
Witvrouw, M.; Pannecouque, C.; De Clercq, E.; Fernández-Alvarez, E.; Marco, J.L. Inhibition of human immunodeficiency virus type (HIV-1) replication by some diversely functionalized spirocyclopropyl derivatives. Arch. Pharm. (Weinheim), 1999, 332(5), 163-166.
[http://dx.doi.org/10.1002/(SICI)1521-4184(19995)332:5<163:AID-ARDP163>3.0.CO;2-2] [PMID: 10366901]
[7]
Pinto, I.L.; West, A.; Debouckm, C.M.; Dilella, A.G.; Gorniak, J.G.O. ʹDonell, K.C.; OʹShannessy, D.J.; Patel, A.; Jarvest, R.L.; Novel, selective mechanism-based inhibitors of the herps proteases. Bioorg. Med. Chem. Lett., 1996, 6, 2467-2472.
[http://dx.doi.org/10.1016/0960-894X(96)00456-8]
[8]
Madkour, H.M.F. Simple one-pot syntheses of heterocyclic systems from (4Z)-2-phenyl-4-(thien-2-ylmethylene)-1,3(4H)-oxazol-5-one. Chem. Pap., 2002, 56, 313-319.
[9]
Jat, R.L.; Mishra, R.; Pathak, D. Synthesis and anticancer activity of 4-benzylidene-2-phenyloxazol-5(4H)-one derivatives Intl. J.Pharm. Pharm. Sci.,, 2012, 4, 0975-1491.
[10]
Balzani, E.; Robinson, R. The preparation of certain azlactones. Chem. Ind., 1954, 1954, 191.
[11]
Baltazzi, E.; Davis, E. Cyclodehydrations with complexes of sulfur trioxide. Synthesis of azlactones. Chem. Ind., 1962, 929.
[12]
Boyd, G.V.; Wright, P.H. Cyclisation of -acylamino-acids in the presence of perchloric acid to give 5-oxo- 2 -oxazolinium perchlorates. J. Chem. Soc. Perkin Trans. I, 1972, 7, 909-913.
[http://dx.doi.org/10.1039/P19720000909] [PMID: 4338275]
[13]
Rao, Y.S. Reactions in polyphosphoric acid. I. New stereospecific synthesis of the E isomers of 2-phenyl-4-arylmethylene-2-oxazolin-5-ones. J. Org. Chem., 1976, 41, 722-725.
[http://dx.doi.org/10.1021/jo00866a037]
[14]
Chen, F.; Kuroda, K.; Benoiton, N. A simple preparation of 5-oxo-4,5-dihydro-1,3-oxazoles (oxazolones). Synthesis, 1979, 1979, 230-232.
[http://dx.doi.org/10.1055/s-1979-28634]
[15]
Rao, P.S.; Venkatratnam, R. Anhydrous zinc chloride catalysed synthesis of 2-phenyl-4-arylidene-5(4H)-oxazolones. J. Chem. Sec. B, 1994, 33, 984.
[16]
Monk, K.A.; Sarapa, D.; Mohan, R.S. Bismuth (III) acetate: A new catalyst for preparation of azlactones via the Erlenmeyer synthesis. Synth. Commun., 2000, 30, 3167-3170.
[http://dx.doi.org/10.1080/00397910008086926]
[17]
Khodaei, M.M.; Khosropour, A.R.; Jomor, S.J.H. Efficient and chemoselective conversion of aryl aldehydes to their azalactones catalysed by Bi(III) salts under solvent free conditions. J. Chem. Res. (S), 2003, 2003, 638-641.
[18]
Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Calcium acetate catalyzed synthesis of 4-arylidene-2-phenyl-5(4H)- oxazolones under solvent-free conditions. Tetrahedron Lett., 2004, 45, 425-427.
[http://dx.doi.org/10.1016/j.tetlet.2003.10.125]
[19]
Bautista, F.M.; Campelo, J.M.; Garcia, A.; Luna, D.; Marinas, J.M.; Romero, A.A. Study on dry-media microwave azalactone synthesis on different supported KF catalysts: Influence of textural and acid-base properties of supports. J. Chem. Soc., Perkin Trans. 2, 2002, 2002, 227-234.
[http://dx.doi.org/10.1039/b109413k]
[20]
Yu, C.; Zhou, B.; Su, W.; Xu, Z. Erlenmeyer synthesis for azlactones catalyzed by ytterbium(III) triflate under solvent-free conditions. Synth. Commun., 2006, 36, 3447-3453.
[http://dx.doi.org/10.1080/00397910600941521]
[21]
Khosropour, A.R.; Khodaei, M.M.; Jomor, S.J.H. A new, efficient and chemoselective one-pot protocol for synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones from aryl aldehyde bisulfite adducts promoted by POCl3. J. Heterocycl. Chem., 2008, 45, 683-686.
[http://dx.doi.org/10.1002/jhet.5570450308]
[22]
Tikdari, A.M.; Fozooni, S.; Hamidian, H. Dodecatungstophosphoric acid (H3PW12O40), samarium and ruthenium (III) chloride catalyzed synthesis of unsaturated 2-phenyl-5(4H)-oxazolone derivatives under solvent-free conditions. Molecules, 2008, 13(12), 3246-3252.
[http://dx.doi.org/10.3390/molecules13123246] [PMID: 19104489]
[23]
Conway, P.A.; Devine, K.; Paradisi, F. A simple and efficient method for the synthesis of Erlenmeyer azlactones. Tetrahedron, 2009, 65, 2935-2938.
[http://dx.doi.org/10.1016/j.tet.2009.02.011]
[24]
Chavez, F.; Kennedy, N.; Rawalpally, T.; Williamson, R.T.; Cleary, T. Substituents effect on the erlenmeyer-plöchl reaction: Understanding an observed process reaction time. Org. Process Res. Dev., 2010, 14, 579-584.
[http://dx.doi.org/10.1021/op100032s]
[25]
Cleary, T.; Rawalpally, T.; Kennedy, N.; Chavez, F. Catalyzing the Erlenmeyer Plöchl reaction: Organic bases versus sodium acetate. Tetrahedron Lett., 2010, 51, 1533-1536.
[http://dx.doi.org/10.1016/j.tetlet.2009.11.125]
[26]
Cleary, T.; Brice, J.; Kennedy, N.; Chavez, F. One-pot process to Z-α-benzoylamino-acrylic acid methyl esters via potassium phosphate-catalyzed Erlenmeyer reaction. Tetrahedron Lett., 2010, 51, 625-628.
[http://dx.doi.org/10.1016/j.tetlet.2009.11.081]
[27]
Taylor, L.D.; Platt, T.E. A convenient synthesis of 5-oxazolones: 2-phenyl-5-oxazolone. Org. Prep. Proced. Int., 1969, 1, 217-219.
[28]
Goswami, L.; Tripathy, P.K. Synthesis of Erlenmeyer azlactones using arylsulphonyl chloride as cyclocondensing agent. Indian J. Heterocycl. Chem., 2015, 24, 281-282.
[29]
Siddaiah, V.; Basha, G.M.; Sudhakar, D.; Srinuvasarao, R.; Kumar, Y.S. Practical synthesis of 4-benzylidene-2-phenyl-5(4H)-oxazolones. Synth. Commun., 2013, 43, 2191-2197.
[http://dx.doi.org/10.1080/00397911.2012.696301]
[30]
Rostami, M.; Khosropour, A.; Mirkhani, V.; Moghadam, M.; Tangestaninejad, S.; Mohammadpoor-Baltork, I. Organic-inorganic hybrid polyoxometalates: efficient, heterogeneous and reusable catalysts for solvent-free synthesis of azlactones. Applied Catal. A, 2011, 397, 27-34.
[http://dx.doi.org/10.1016/j.apcata.2011.02.004]
[31]
Shelke, A.D.; Devhade, J.B. Ultrasound assisted an efficient synthesis of azlactone derivatives catalyzed by ionic liquid. Chem. Biol. Interact., 2016, 6, 157-161.
[32]
Pal, R. Fruit juice: A natural, green and biocatalyst system in organic synthesis. Open J. Org. Chem., 2013, 1, 47-56.
[http://dx.doi.org/10.12966/ojoc.10.02.2013]
[33]
Deshmukh, M.B.; Patil, S.S.; Jadhav, S.D.; Pawar, P.B. Green approach for Knoevenagel condensation of aromatic aldehydes. Synth. Commun., 2012, 42, 1177-1183.
[http://dx.doi.org/10.1080/00397911.2010.537423]
[34]
Patil, S.; Jadhav, S.D.; Deshmuk, M.B. Natural acid catalyzed multi-component reactions as a green approach. Arch. Appl. Sci. Res., 2011, 3, 203-208.
[35]
Patil, S.; Jhadav, S.D.; Patil, U.P. Natural acid catalyzed synthesis of schiff base under solvent-free condition: As a green approach. Arch. Appl. Sci. Res., 2012, 4, 1074-1078.
[36]
Sachdeva, H.; Saroj, R.; Khaturia, S.; Dwivedi, D. Environeconomic synthesis and characterization of some new 1,2,4-triazole derivatives as organic fluorescent materials and potent fungicidal agents. Org. Chem. Int.,, 2013, 2013, ID 659107.
[37]
Prasanna, G.L.; Rao, B.V.D.; Reddy, A.G.; Rao, M.V.B.; Pal, M. Lemon juice mediated reaction under ultrasound irradiation: synthesis of indolofuroquinoxalines as potential anticancer agents. Mini Rev. Med. Chem., 2019, 19(8), 671-678.
[http://dx.doi.org/10.2174/1389557518666181029100044] [PMID: 30370847]
[38]
Kumar; S.K.; Rambabu, D.; Kumar, C.H.V.; Sreenivas, B.Y.; Prasad, K.R.S.; Rao, M.V.B.; Pal, M.; Catalysis by Amberlyst-15 under ultrasound in water: A green synthesis of 1,2,4-benzothiadiazine-1,1-dioxides and their spiro derivatives. RSC Advances, 2013, 3, 24863-24867.
[http://dx.doi.org/10.1039/c3ra44703k]
[39]
Nelson, C.E. Lemon juice composition, US patent application number US2215334A, 1938.
[40]
Sharma, P.; Rashmi, S.; Kumar, G.V. Rapid synthesis of amides from ketoximes using citric acid monohydrate over TBAB under green chemistry conditions. J. Adv. Chem. Sci., 2016, 2, 180-182.
[41]
Riordan, J.M.; Stammer, C.H. Synthesis of unsaturated azlactones from N-acylamino acids. J. Org. Chem., 1974, 39(5), 654-659.
[http://dx.doi.org/10.1021/jo00919a017] [PMID: 4833501]
[42]
Blanco-Lomas, M.; Campos, P.J.; Sampedro, D. Benzylidene-oxazolones as molecular photoswitches. Org. Lett., 2012, 14(17), 4334-4337.
[http://dx.doi.org/10.1021/ol301741g] [PMID: 22877084]
[43]
Riordan, J.M.; Stammer, C.H. The direct conversion of N-acyl α-amino acids into N-acyl α,β-unsaturated α-amino acids. Tetrahedron Lett., 1971, 12, 4969-4972.
[http://dx.doi.org/10.1016/S0040-4039(01)97602-6]
[44]
Parveen, M.; Ahmad, F.; Malla, A.M.; Azaz, S.; Silva, M.R.; Silva, P.S.P. [Et3NH][HSO4]-mediated functionalization of hippuric acid: An unprecedented approach to 4-arylidene-2-phenyl-5(4H)-oxazolones. RSC Advances, 2015, 5, 52330-52346.
[http://dx.doi.org/10.1039/C5RA09290F]
[45]
Xie, L-Y.; Li, Y-J.; Qu, J.; Duan, Y.; Hu, J.; Liu, K-J.; Cao, Z.; He, W-M. A base-free, ultrasound accelerated one-pot synthesis of 2-sulfonylquinolines in water. Green Chem., 2017, 19, 5642-5646.
[http://dx.doi.org/10.1039/C7GC02304A]
[46]
Wu, C.; Lu, L-H.; Peng, A-Z.; Jia, G-K.; Peng, C.; Cao, Z.; Tang, Z.; He, W-M.; Xu, X. Ultrasound-promoted Brønsted acid ionic liquid-catalyzed hydrothiocyanation of activated alkynes under minimal solvent conditions. Green Chem., 2018, 20, 3683-3688.
[http://dx.doi.org/10.1039/C8GC00491A]
[47]
Mason, T.J.; Peters, D. Practical Sonochemistry; Ellis Horwood: New York, NY, USA, 1991.
[48]
Mason, T.J. Sonochemistry and the environment - providing a “green” link between chemistry, physics and engineering. Ultrason. Sonochem., 2007, 14(4), 476-483.
[http://dx.doi.org/10.1016/j.ultsonch.2006.10.008] [PMID: 17207652]
[49]
Schiller, J.H.; Gandara, D.R.; Goss, G.D.; Vokes, E.E. Non-small-cell lung cancer: Then and now. J. Clin. Oncol., 2013, 31(8), 981-983.
[http://dx.doi.org/10.1200/JCO.2012.47.5772] [PMID: 23401450]
[50]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[51]
Zhang, N.; Yin, Y.; Xu, S-J.; Chen, W-S. 5-Fluorouracil: Mechanisms of resistance and reversal strategies. Molecules, 2008, 13(8), 1551-1569.
[http://dx.doi.org/10.3390/molecules13081551] [PMID: 18794772]
[52]
Mukherjee, A.K.; Rao, L.; Homami, S.S.; Joseph, K. Reactions of unsaturated azlactones with sulfur nucleophiles: Some observations. Can. J. Chem., 1994, 72, 1384-1387.
[http://dx.doi.org/10.1139/v94-173]


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VOLUME: 22
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