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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Research Article

Development of New IDO Inhibitors with Coumarin Pyrimidine Scaffolds as the Potential Anti Cancer Agents

Author(s): Radhika Chelamalla* and Ajitha Makula

Volume 16 , Issue 8 , 2020

Page: [1172 - 1180] Pages: 9

DOI: 10.2174/1573407216666191216154856

Price: $65

Abstract

Background: Progress in the developments of pyrimidine-coumarin moiety as an IDO inhibitor is still continuing with an outcome of the good scaffold as pyrimidine as well as coumarin individually for anticancer activity. Hence we proposed a suitable approach for the synthesis of pyrimidinecoumarin moieties in a combined form from the results of docking studies.

Objective: As part of our ongoing research towards the development of novel cytotoxic agents, the synthesis and cytotoxic activity of a series of N'-(1-(6-methyl-2-oxo/thioxo-4-sub phenyl-1,2,3,4- tetrahydropyrimidin-5-yl)vinyl)-2-oxo-2H-chromene-3-carbohydrazide derivatives are discussed in this study.

Methods: N'-(1-(6-methyl-2-oxo/thioxo-4-sub phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)vinyl)-2-oxo- 2H-chromene-3-carbohydrazide derivatives were designed, synthesized and evaluated for cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR, Mass spectroscopy. All the synthesized compounds were evaluated using in vitro MTT assay against HeLa and HepG2 cell lines.

Results: Compound 6g showed inhibitory activity against IDO with IC50 values at nanomolar range in docking studies and compounds 6g and 6f also showed significant cytotoxic activity on human cancer cell lines like HepG2 and HeLa using in vitro MTT assay.

Conclusion: This work showed that the coumarin containing pyrimidine derivatives are found to be the most potent against IDO through docking studies and cytotoxic against cell lines compared with cisplatin. This might give the information for the development of new series of compounds against IDO.

Keywords: Coumarin, pyrimidine, indolamine-2, 3-dioxygensase, docking, cytotoxic activity, MTT assay.

Graphical Abstract
[1]
Vacchelli, E.; Aranda, F.; Eggermont, A.; Sautès-Fridman, C.; Tartour, E.; Kennedy, E.P.; Platten, M.; Zitvogel, L.; Kroemer, G.; Galluzzi, L. Trial watch: IDO inhibitors in cancer therapy. OncoImmunology, 2014, 3(10), e957994.
[http://dx.doi.org/10.4161/21624011.2014.957994] [PMID: 25941578]
[2]
Ferris, R.L.; Blumenschein, G., Jr; Fayette, J.; Guigay, J.; Colevas, A.D.; Licitra, L.; Harrington, K.; Kasper, S.; Vokes, E.E.; Even, C.; Worden, F.; Saba, N.F.; Iglesias Docampo, L.C.; Haddad, R.; Rordorf, T.; Kiyota, N.; Tahara, M.; Monga, M.; Lynch, M.; Geese, W.J.; Kopit, J.; Shaw, J.W.; Gillison, M.L. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med., 2016, 375(19), 1856-1867.
[http://dx.doi.org/10.1056/NEJMoa1602252] [PMID: 27718784]
[3]
Moffett, J.R.; Namboodiri, M.A. Tryptophan and the immune response. Immunol. Cell Biol., 2003, 81(4), 247-265.
[http://dx.doi.org/10.1046/j.1440-1711.2003.t01-1-01177.x] [PMID: 12848846]
[4]
Moon, Y.W.; Hajjar, J.; Hwu, P.; Naing, A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J. Immunother. Cancer, 2015, 3(51), 51.
[http://dx.doi.org/10.1186/s40425-015-0094-9] [PMID: 26674411]
[5]
Hosamani, K.M.; Reddy, D.S.; Devarajegowda, H.C. Microwave-assisted synthesis of new fluorinated coumarin-pyrimidine hybrids as potent anticancer agents, their DNA cleavage and X-ray crystal studies. RSC. Adv., 2015, 5(15), 11261-11271.
[http://dx.doi.org/10.1039/C4RA12222D]
[6]
Kaur, R.; Kaur, P.; Sharma, S.; Singh, G.; Mehndiratta, S.; Bedi, P.M.; Nepali, K. Anti-cancer pyrimidines in diverse scaffolds: A review of patent literature. Rec. Pat. Anticancer Drug Discov., 2015, 10(1), 23-71.
[http://dx.doi.org/10.2174/1574892809666140917104502] [PMID: 25230072]
[7]
Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: A promising scaffold for anticancer agents. Anticancer. Agents Med. Chem., 2015, 15(8), 1032-1048.
[http://dx.doi.org/10.2174/1871520615666150101125503] [PMID: 25553437]
[8]
Ferns, D.M.; Kema, I.P.; Buist, M.R.; Nijman, H.W.; Kenter, G.G.; Jordanova, E.S. Indoleamine-2,3-Dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival. OncoImmunology, 2015, 4(2), e981457.
[http://dx.doi.org/10.4161/2162402X.2014.981457] [PMID: 25949879]
[9]
Kulkarni, K.; Kakarla, R.K.; Babu, A.V.; Sreelatha, V.; Jyothi, V.; Sadanandam, P. Synthesis and biological evaluation of pyrazole amides fused combretastatin derivatives as anticancer agents. Curr. Bioact. Compd., 2018, 14(4), 357-363.
[http://dx.doi.org/10.2174/1573407213666170405122545]
[10]
Kamala, K.V.; Hemantkumar, D.I.; Sneha, R.S.; Jayesh, A.S.; Dhaivat, H.P. Milee. A. 2-((1H-1, 2, 3-triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones: Design, synthesis and evaluation as anti-cancer agents. Curr. Bioact. Compd., 2018, 14(3), 254-263.
[http://dx.doi.org/10.2174/1573407213666170329131557]
[11]
Sanjiv, K.; Aakash, D.; Balasubramanian, N. A review on synthesis, anticancer and antiviral potentials of pyrimidine derivatives. Curr. Bioact. Compd., 2019, 15(3), 289-303.
[http://dx.doi.org/10.2174/1573407214666180124160405]
[12]
Garrett, M.M.; David, S.G.; Robert, S.H.; Ruth, H.; William, E.H.; Richard, K.B.; Arthur, J.O. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1998, 19, 1639.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639:AID-JCC10>3.0.CO;2-B]
[13]
Abdel-Wahab, B.F.; Mohamed, H.A.; Farhat, A.A. Ethyl coumarin-3-carboxylate: Synthesis and chemical properties. Org. Commun., 2014, 7(1), 1-27.
[14]
Radhika, C.; Venkatesham, A.; Anantha, K.C.D. Synthesis and antiinflammatory activity of pyrimidine fused thiazolidinone derivatives. IJAPR, 2014, 5(2), 99-103.
[15]
Radhika, C.; Venkatesham, A. Anantha K.C.D. Synthesis and Biological activity of new 5-methyl-3-oxo-N2[5′-carbonyl-(4′-Aryl-6‘methyl)-1’,2′,3′,4′–tetrahydropyrimidine-2′-one]pyrazolidines. JAPER, 2014, 4(1), 1-4.
[16]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[17]
Scudiero, D.A.; Shoemaker, R.H.; Paull, K.D.; Monks, A.; Tierney, S.; Nofziger, T.H.; Currens, M.J.; Seniff, D.; Boyd, M.R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res., 1988, 48(17), 4827-4833.
[PMID: 3409223]
[18]
Alley, M.C.; Scudiero, D.A.; Monks, A.; Hursey, M.L.; Czerwinski, M.J.; Fine, D.L.; Abbott, B.J.; Mayo, J.G.; Shoemaker, R.H.; Boyd, M.R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 1988, 48(3), 589-601.
[PMID: 3335022]

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