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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Cytotoxicity, Antioxidant and Antimicrobial Activity of Indole Based Novel Small Molecules

Author(s): Aslıhan Kurt-Kızıldoğan, Çiğdem Otur, Can Yılmaz, Sevki Arslan, Dogukan Mutlu, Arif Kivrak*, Muheb Algso, Abdussamet Kayhan, Doğan Çetin and Metin Konus*

Volume 18, Issue 5, 2021

Published on: 09 November, 2020

Page: [461 - 470] Pages: 10

DOI: 10.2174/1570180817999201109203226

Price: $65

Abstract

Aims: In this study experiments were carried out to explore antioxidant, antimicrobial, cytotoxic properties of novel indole derivative 1-ethyl-2-phenyl-3-phenylethyl-3-thiophen-2-yl-1Hindole (EPI) together with its effect on glutathione S-transferases (GST) activities in human liver carcinoma (HepG2) cells.

Background: Indoles probably represent one of the most important heterocyclic structures that have been attracting the interest of many scientists in drug discovery.

Objective: The present study was carried out to explore antioxidant, antimicrobial, cytotoxic properties of novel indole derivative 1-ethyl-2-phenyl-3-phenylethyl-3-thiophen-2-yl-1H-indole (EPI) and its effect on glutathione S-transferases (GST) activities in human liver carcinoma (HepG2) cells.

Materials and Methods: Pd-catalyst Sonogashira coupling reactions, MTT Assay, Antioxidant capacity test, Antimicrobial test, GST enzyme activity test.

Results: 1-ethyl-2-phenyl-3-(phenylethynyl)-1H-indole had antioxidant and antimicrobial properties. It displayed significant induction in glutathione S-transferases (GST) enzyme activity in human liver cancer cell lines (HepG2), but cytotoxic effect on all tested cancer cell lines could not be observed.

Conclusion: All of these results showed that 1-ethyl-2-phenyl-3-(phenylethynyl)-1H-indole had antioxidant and antimicrobial properties without cytotoxic effect, which could make it a promising active component with further studies.

Keywords: Indole, heteroaromatic compounds, antioxidant, cytotoxicity, antimicrobial, small molecules.

Graphical Abstract
[1]
Netz, N.; Opatz, T. Marine Indole Alkaloids. Mar. Drugs, 2015, 13(8), 4814-4914.
[http://dx.doi.org/10.3390/md13084814] [PMID: 26287214]
[2]
Carbas, B.B.; Kivrak, A.; Kayak, E. Electrosynthesis of a new indole based donor-acceptor-donor type polymer and investigation of its electrochromic properties. Mater. Chem. Phys., 2017, 188, 68-74.
[http://dx.doi.org/10.1016/j.matchemphys.2016.12.040]
[3]
Shi, Z.; Nie, K.R.; Liu, C.; Zhang, M.Z.; Zhang, W.H. Biological activities of 3-(5-oxazolyl)indole natural products and advances on synthesis of its derivatives. Youji Huaxue, 2020, 40, 327-338.
[http://dx.doi.org/10.6023/cjoc201907047]
[4]
Karaaslan, C.; Kadri, H.; Coban, T.; Suzen, S.; Westwell, A.D. Synthesis and antioxidant properties of substituted 2-phenyl-1H-indoles. Bioorg. Med. Chem. Lett., 2013, 23(9), 2671-2674.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.090] [PMID: 23540647]
[5]
Ali, N.A.S.; Dar, B.A.; Pradhan, V.; Farooqui, M. Chemistry and biology of indoles and indazoles: A mini-review. Mini Rev. Med. Chem., 2013, 13(12), 1792-1800.
[http://dx.doi.org/10.2174/1389557511313120009] [PMID: 22625410]
[6]
Suzen, S. Antioxidant activities of synthetic indole derivatives and possible activity mechanisms. Bioactive Heterocycles V. Topics in Heterocyclic Chemistry; Khan, M.T.H., Ed.; Springer: Berlin, Heidelberg, 2007, Vol. 11, pp. 145-178.
[http://dx.doi.org/10.1007/7081_2007_074]
[7]
Singh, T.P.; Singh, O.M. Recent progress in biological activities of indole and indole alkaloids. Mini Rev. Med. Chem., 2018, 18(1), 9-25.
[PMID: 28782480]
[8]
Yuan, W.; Yu, Z.; Song, W.; Li, Y.; Fang, Z.; Zhu, B.; Li, X.; Wang, H.; Hong, W.; Sun, N. Indole-core-based novel antibacterial agent targeting FtsZ. Infect. Drug Resist., 2019, 12, 2283-2296.
[http://dx.doi.org/10.2147/IDR.S208757] [PMID: 31413605]
[9]
Guler, M.; Turkoglu, V.; Kivrak, A. A novel glucose oxidase biosensor based on poly(2,2′; 5′,2” -terthiophene-3 '-carbaldehyde) modified electrode. Int. J. Biol. Macromol., 2015, 79, 262-268.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.04.042] [PMID: 25934105]
[10]
Sondhi, S.M.; Dinodia, M.; Kumar, A. Synthesis, anti-inflammatory and analgesic activity evaluation of some amidine and hydrazone derivatives. Bioorg. Med. Chem., 2006, 14(13), 4657-4663.
[http://dx.doi.org/10.1016/j.bmc.2006.02.014] [PMID: 16504522]
[11]
Biradar, J.S.; Sasidhar, B.S.; Parveen, R. Synthesis, antioxidant and DNA cleavage activities of novel indole derivatives. Eur. J. Med. Chem., 2010, 45(9), 4074-4078.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.067] [PMID: 20594623]
[12]
Shirinzadeh, H.; Altanlar, N.; Yucel, N.; Ozden, S.; Suzen, S. Antimicrobial evaluation of indole-containing hydrazone derivatives, zeitschrift fur naturforschung section c-a. J. Biosci., 2011, 66, 340-344.
[13]
Patil, P.; Nimonkar, A.; Akamanchi, K.G. Aryl-free radical-mediated oxidative arylation of naphthoquinones using o-iodoxybenzoic acid and phenylhydrazines and its application toward the synthesis of benzocarbazoledione. J. Org. Chem., 2014, 79(5), 2331-2336.
[http://dx.doi.org/10.1021/jo500131h] [PMID: 24512551]
[14]
Mokbel, K.; Wazir, U.; Mokbel, K. Chemoprevention of prostate cancer by natural agents: Evidence from molecular and epidemiological studies. Anticancer Res., 2019, 39(10), 5231-5259.
[http://dx.doi.org/10.21873/anticanres.13720] [PMID: 31570421]
[15]
Lim, H.R.; Kim, S.Y.; Jeon, E.H.; Kim, Y.L.; Shin, Y.M.; Koo, T-S.; Park, S.J.; Hong, K.B.; Choi, S. A highly sensitive fluorescent probe that quantifies transthyretin in human plasma as an early diagnostic tool of Alzheimer’s disease. Chem. Commun. (Camb.), 2019, 55(70), 10424-10427.
[http://dx.doi.org/10.1039/C9CC04172A] [PMID: 31407744]
[16]
Doens, D.; Valdés-Tresanco, M.E.; Vasquez, V.; Carreira, M.B.; De La Guardia, Y.; Stephens, D.E.; Nguyen, V.D.; Nguyen, V.T.; Gu, J.; Hegde, M.L.; Larionov, O.V.; Valiente, P.A.; Lleonart, R.; Fernández, P.L. Hexahydropyrrolo[2,3-b]indole compounds as potential therapeutics for Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(10), 4250-4263.
[http://dx.doi.org/10.1021/acschemneuro.9b00297] [PMID: 31545596]
[17]
Zhang, M.Z.; Chen, Q.; Yang, G.F. A review on recent developments of indole-containing antiviral agents. Eur. J. Med. Chem., 2015, 89, 421-441.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.065] [PMID: 25462257]
[18]
Rashid, H.U.; Xu, Y.; Muhammad, Y.; Wang, L.; Jiang, J. Research advances on anticancer activities of matrine and its derivatives: An updated overview. Eur. J. Med. Chem., 2019, 161, 205-238.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.037] [PMID: 30359819]
[19]
Kumari, A.; Singh, R.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives. Bioorg. Chem., 2019, 89, 103021.
[http://dx.doi.org/10.1016/j.bioorg.2019.103021] [PMID: 31176854]
[20]
Brown, G.D.; Denning, D.W.; Gow, N.A.R.; Levitz, S.M.; Netea, M.G.; White, T.C. Hidden killers: Human fungal infections. Sci. Transl. Med., 2012, 4(165), 165rv13.
[http://dx.doi.org/10.1126/scitranslmed.3004404] [PMID: 23253612]
[21]
Holland, T.; Fowler, V.G., Jr; Shelburne, S.A., III Invasive gram-positive bacterial infection in cancer patients. Clin. Infect. Dis., 2014, 59(Suppl. 5), S331-S334.
[http://dx.doi.org/10.1093/cid/ciu598] [PMID: 25352626]
[22]
Sivalingam, P.; Hong, K.; Pote, J.; Prabakar, K. Extreme environment streptomyces: Potential sources for new antibacterial and anticancer drug leads? Int. J. Microbiol., 2019, 2019, 5283948.
[http://dx.doi.org/10.1155/2019/5283948] [PMID: 31354829]
[23]
de Kraker, M.E.A.; Stewardson, A.J.; Harbarth, S. Will 10 million people die a year due to antimicrobial resistance by 2050? PLoS Med., 2016, 13(11), e1002184.
[http://dx.doi.org/10.1371/journal.pmed.1002184] [PMID: 27898664]
[24]
Kumar, S.; Kaur, P.; Kumar, V. Indium reagents in heterocyclic chemistry. Curr. Org. Chem., 2005, 9, 1205-1235.
[http://dx.doi.org/10.2174/1385272054863989]
[25]
Khanna, L.; Singhal, S.; Jain, S.C.; Khanna, P. Spiro-indole-coumarin hybrids: Synthesis, adme, dft, nbo studies and in silico screening through molecular docking on dna g-quadruplex. ChemistrySelect, 2020, 5(11), 3420-3433.
[http://dx.doi.org/10.1002/slct.201904783] [PMID: 32328514]
[26]
Rajaraman, D.; Sundararajan, G.; Loganath, N.K.; Krishnasamy, K. Synthesis, molecular structure, DFT studies and antimicrobial activities of some novel 3-(1-(3,4-dimethoxyphenethyl)-4,5-diphenyl-1H-imidazol-2-yl)-1H-indole derivatives and its molecular docking studies. J. Mol. Struct., 2017, 1127, 597-610.
[http://dx.doi.org/10.1016/j.molstruc.2016.08.021]
[27]
ElBordiny, H.S.; El-Miligy, M.M.; Kassab, S.E.; Daabees, H.; Mohamed Ali, W.A.; Abdelhamid Mohamed El-Hawash, S. Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors. Eur. J. Med. Chem., 2018, 145, 594-605.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.026] [PMID: 29339254]
[28]
Zhu, W.; Bao, X.; Ren, H.; Da, Y.; Wu, D.; Li, F.; Yan, Y.; Wang, L.; Chen, Z. N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation. Eur. J. Med. Chem., 2016, 115, 161-178.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.021] [PMID: 27017546]
[29]
Yan, J.; Chen, J.; Zhang, S.; Hu, J.; Huang, L.; Li, X. Synthesis, evaluation, and mechanism study of novel indole-chalcone derivatives exerting effective antitumor activity through microtubule destabilization in vitro and in vivo. J. Med. Chem., 2016, 59(11), 5264-5283.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00021] [PMID: 27149641]
[30]
Cihan-Üstündağ, G.; Gürsoy, E.; Naesens, L.; Ulusoy-Güzeldemirci, N.; Çapan, G. Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones. Bioorg. Med. Chem., 2016, 24(2), 240-246.
[http://dx.doi.org/10.1016/j.bmc.2015.12.008] [PMID: 26707844]
[31]
Zora, M.; Demirci, D.; Kivrak, A.; Kelgokmen, Y. One-pot synthesis of 4-(phenylselanyl)-substituted pyrazoles. Tetrahedron Lett., 2016, 57, 993-997.
[http://dx.doi.org/10.1016/j.tetlet.2016.01.071]
[32]
Konus, M.; Aydemir, S.; Yilmaz, C.; Kivrak, A.; Kizildogan, A.K.; Arpaci, P.U. Synthesis and evaluation of antioxidant, antimicrobial and anticancer properties of 2-(prop-2-yn-1-yloxy)benzaldehyde derivatives. Lett. Org. Chem., 2019, 16, 415-423.
[http://dx.doi.org/10.2174/1570178616666181116100232]
[33]
Algso, M.A.S.; Kivrak, A.; Konus, M.; Yilmaz, C.; Kurt-Kizildogan, A. Synthesis and biological evaluation of novel benzothiophene derivatives. J. Chem. Sci., 2018, 130, 119.
[http://dx.doi.org/10.1007/s12039-018-1523-3]
[34]
Townsend, D.M.; Tew, K.D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene, 2003, 22(47), 7369-7375.
[http://dx.doi.org/10.1038/sj.onc.1206940] [PMID: 14576844]
[35]
Lu, Y.; Gao, X. Multiple mechanisms responsible for differential susceptibilities of Sitobion avenae (Fabricius) and Rhopalosiphum padi (Linnaeus) to pirimicarb. Bull. Entomol. Res., 2009, 99(6), 611-617.
[http://dx.doi.org/10.1017/S0007485309006725] [PMID: 19413913]
[36]
Wolfe, K.L.; Liu, R.H. Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J. Agric. Food Chem., 2007, 55(22), 8896-8907.
[http://dx.doi.org/10.1021/jf0715166] [PMID: 17902627]
[37]
Baglai, I.; Maraval, V.; Bijani, C.; Saffon-Merceron, N.; Voitenko, Z.; Volovenko, Y.M.; Chauvin, R. Enhanced π-frustration in carbo-benzenic chromophores. Chem. Commun. (Camb.), 2013, 49(75), 8374-8376.
[http://dx.doi.org/10.1039/c3cc43204a] [PMID: 23936897]
[38]
Shi, H.; Niki, E. Stoichiometric and kinetic studies on Ginkgo biloba extract and related antioxidants. Lipids, 1998, 33(4), 365-370.
[http://dx.doi.org/10.1007/s11745-998-0216-8] [PMID: 9590623]
[39]
Prieto, P.; Pineda, M.; Aguilar, M. Spectrophotometric quantitation of antioxidant capacity through the formation of a phosphomolybdenum complex: Specific application to the determination of vitamin E. Anal. Biochem., 1999, 269(2), 337-341.
[http://dx.doi.org/10.1006/abio.1999.4019] [PMID: 10222007]
[40]
Benzie, I.F.F.; Strain, J.J. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal. Biochem., 1996, 239(1), 70-76.
[http://dx.doi.org/10.1006/abio.1996.0292] [PMID: 8660627]
[41]
Sen, A.; Ozgun, O.; Arinç, E.; Arslan, S. Diverse action of acrylamide on cytochrome P450 and glutathione S-transferase isozyme activities, mRNA levels and protein levels in human hepatocarcinoma cells. Cell Biol. Toxicol., 2012, 28(3), 175-186.
[http://dx.doi.org/10.1007/s10565-012-9214-1] [PMID: 22392284]
[42]
Algso, M.A.S.; Kivrak, A. New strategy for the synthesis of 3-ethynyl-2-(thiophen-2-yl)benzothiophene derivatives. Chem. Pap., 2019, 73, 977-985.
[http://dx.doi.org/10.1007/s11696-018-0640-2]
[43]
Konus, M.; Algso, M.A.S.; Kavak, E.; Kurt-Kizildogan, A.; Yilmaz, C.; Kivrak, A. Design, synthesis, and in vitro evaluation of thieno a dibenzothiophene derivatives. ChemistrySelect, 2020, 5, 3700-3709.
[http://dx.doi.org/10.1002/slct.202000685]
[44]
Zora, M.; Kivrak, A.; Yazici, C. Synthesis of pyrazoles via electrophilic cyclization. J. Org. Chem., 2011, 76(16), 6726-6742.
[http://dx.doi.org/10.1021/jo201119e] [PMID: 21739980]
[45]
Amorati, R.; Valgimigli, L. Advantages and limitations of common testing methods for antioxidants. Free Radic. Res., 2015, 49(5), 633-649.
[http://dx.doi.org/10.3109/10715762.2014.996146] [PMID: 25511471]
[46]
Amorati, R.; Menichetti, S.; Viglianisi, C.; Foti, M.C. Proton-electron transfer pathways in the reactions of peroxyl and dpph˙ radicals with hydrogen-bonded phenols. Chem. Commun. (Camb.), 2012, 48(97), 11904-11906.
[http://dx.doi.org/10.1039/c2cc36531f] [PMID: 23125978]
[47]
Fan, M.; Chen, G.; Zhang, Y.; Nahar, L.; Sarker, S.D.; Hu, G.; Guo, M. Antioxidant and anti-proliferative properties of hagenia abyssinica roots and their potentially active components. Antioxidants, 2020, 9(2), 143.
[http://dx.doi.org/10.3390/antiox9020143] [PMID: 32041310]
[48]
Wan, Y.; Li, Y.; Yan, C.; Yan, M.; Tang, Z. Indole: A privileged scaffold for the design of anti-cancer agents. Eur. J. Med. Chem., 2019, 183111691.
[http://dx.doi.org/10.1016/j.ejmech.2019.111691] [PMID: 31536895]
[49]
Honzel, D.; Carter, S.G.; Redman, K.A.; Schauss, A.G.; Endres, J.R.; Jensen, G.S. Comparison of chemical and cell-based antioxidant methods for evaluation of foods and natural products: generating multifaceted data by parallel testing using erythrocytes and polymorphonuclear cells. J. Agric. Food Chem., 2008, 56(18), 8319-8325.
[http://dx.doi.org/10.1021/jf800401d] [PMID: 18717566]

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