Design, Synthesis, Anti-Proliferative, Anti-microbial, Anti-Angiogenic Activity and In Silico Analysis of Novel Hydrazone Derivatives

Author(s): Hakan Ünver, Burak Berber*, Rasime Demirel, Ayşe T. Koparal.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 13 , 2019

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Graphical Abstract:


Background: Cancer is the second leading cause of death globally. Hydrazone and hydrazone derivatives have high activity, and for this reason, these compound are greatly used by researchers to synthesize new anti-cancer drug. The aim of this research work is to synthesize novel anticancer agents.

Methods: New hydrazone derivatives were synthesized via a reaction between 3-formylphenyl methyl carbonate and benzhydrazide, 4-methylbenzoic hydrazide, 4-tert-butylbenzoic hydrazide, 4-nitrobenzoic hydrazide and 3- methoxybenzoic hydrazide, and were successfully characterized using elemental analysis, 1H-NMR, 13C-NMR, FT-IR and LC-MS techniques. The synthesized compounds were evaluated for their antimicrobial (some grampositive and -negative bacteria, filamentous fungi and yeasts), anti-proliferative (T47D and HCC1428-breast cancer cells) and anti-angiogenic (HUVEC-endothelial cells) activities. The anti-proliferative activities of the hydrazone compounds R1-R5 were studied on these cell lines by MTT assay. The anti-angiogenic potential of the compounds was determined by the endothelial tube formation assay. To identify structural features related to the anti-proliferative activity of these compounds, 2D-QSAR was performed.

Result: The results indicated that compound R3 exhibited strong anti-angiogenic and anti-proliferative activity on breast cancer cell lines and healthy cell lines. Also, this compound; possessing a tertiary butyl moiety on the hydrazine, exhibited the highest inhibitory effect against all tested microorganisms; in particular, it inhibited Candida albicans at a lower concentration than ketoconazole. Among the investigated compounds, those bearing methyl, tertiary butyl (compound R2, R3) and methoxy (compound R5) moiety were found to be more successful anticandidal derivatives than standard antifungal antibiotics. The QSAR analysis suggested that the tumor specificity of the hydrazone correlated with their molecular weight, lipophilicity, molar refractivity, water solubility, DipolHybrid:(MOPAC) and ExchangeEnergy:(MOPAC). Absorption, Distribution, Metabolism and Elimination (ADME) analysis of the hydrazone compounds showed that they have favorable pharmacokinetic and drug-likeness properties. The ADME results clarify that R3 is the best compound in terms of pharmacokinetic properties. In contrast to other compounds; target prediction analysis of the compound R3 showed inhibitory activity on estrogen-related receptor alpha transcription factor (ESRRA). The target prediction analysis was supported by molinspiration bioactivity score.

Conclusion: The R3 compound is considered to be an important candidate for future studies with its suitability for the Lipinski’s rule of five for drug-likeness, and effective in vitro and in silico results.

Keywords: Hydrazone, anti-microbial activity, QSAR, ADME, anti-angiogenic activity, anti-proliferative.

Society, A.C. Cancer facts & figures 2018; Am. Cancer Soc, 2018.
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; All, E. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
Israel, B.B.; Tilghman, S.L.; Parker-Lemieux, K.; Payton-Stewart, F. Phytochemicals: Current strategies for treating breast cancer. (Review) Oncol. Lett., 2018, 15(5), 7471-7478.
Li, L.Y.; Peng, J.D.; Zhou, W.; Qiao, H.; Deng, X.; Li, Z.H.; Li, J.D.; Fu, Y.D.; Li, S.; Sun, K. Potent hydrazone derivatives targeting esophageal cancer cells. Eur. J. Med. Chem., 2018, 148, 359-371.
Li, L.Y.; Peng, J.D.; Zhou, W.; Qiao, H.; Deng, X.; Li, Z.H.; Li, J.D.; Fu, Y.D.; Li, S.; Sun, K. Zhang, Over expressing miR-19b-1 suppress breast cancer growth by inhibiting tumor microenvironment induced angiogenesis. Int. J. Biochem. Cell Biol., 2018, 97, 43-51.
Koparal, A.T. Anti-angiogenic and antiproliferative properties of the lichen substances (-)-usnic acid and vulpinic acid, Zeitschrift Fur Naturforsch. - Sect. C. J. Biosci., 2015, 70(5-6), 159-164.
Altıntop, M.D.; Özdemir, A.; Atlı, Ö.; Cantürk, Z.; Baysal, M.; Asım Kaplancıklı, Z. Synthesis and evaluation of new thiazole derivatives as potential antimicrobial agents. Lett. Drug Des. Discov., 2016, 13(9), 903-911.
Altintop, M.D.; Ödemir, A.; Turan-Zitouni, G.; Ilgin, S.; Atli, Ö.; Demirel, R.; Kaplancikli, Z.A. novel series of thiazolyl-pyrazoline derivatives: Synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity. Eur. J. Med. Chem., 2015, 92, 342-352.
Wu, J.; Kang, S.; Song, B.; Hu, D.; He, M.; Jin, L.; Yang, S. Synthesis and antibacterial activity against ralstonia solanacearum for novel hydrazone derivatives containing a pyridine moiety. Chem. Cent. J., 2012, 6, 28.
Terzioglu, N.; Gürsoy, A. Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazide. Eur. J. Med. Chem., 2003, 38, 781-786.
Nasr, T.; Bondock, S.; Youns, M. Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives. Eur. J. Med. Chem., 2014, 76, 539-548.
Tian, F.F.; Li, J.H.; Jiang, F.L.; Han, X.L.; Xiang, C.; Ge, Y.S.; Li, L.L.; Liu, Y. The adsorption of an anticancer hydrazone by protein: An unusual static quenching mechanism. RSC Adv, 2012, 2, 501-513.
Kumar, N.; Chauhan, L.S.; Sharma, C.S.; Dashora, N.; Bera, R. Synthesis, analgesic and anti-inflammatory activities of chalconyl-incorporated hydrazone derivatives of mefenamic acid. Med. Chem. Res., 2015, 24, 2580-2590.
Altintop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgin, S.; Atli, Ö.; Demirci, F.; Kaplancikli, Z. A Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents. Molecules, 2014, 19, 14809-14820.
Yurttaş, L.; Kaplancıklı, Z.A.; Göger, G.; Demirci, F. Synthesis and anticandidal evaluation of new benzothiazole derivatives with hydrazone moiety. J. Enzyme Inhib. Med. Chem., 2016, 31, 714-720.
Thomas, A.B.; Nanda, R.K.; Kothapalli, L.P.; Hamane, S.C. Synthesis and biological evaluation of Schiff’s bases and 2-azetidinones of isonocotinyl hydrazone as potential antidepressant and nootropic agents. Arab. J. Chem., 2016, 9, S79-S90.
Sharma, A.; Kumar, V.; Jain, S.; Sharma, P.C. Thiazolidin-4-one and hydrazone derivatives of capric acid as possible anti-inflammatory, analgesic and hydrogen peroxide-scavenging agents. J. Enzyme Inhib. Med. Chem., 2011, 26, 546-552.
Sondhi, S.M.; Dinodia, M.; Rani, R.; Shukla, R.; Raghubir, R. Synthesis, anti-inflammatory and analgesic activity evaluation of some pyrimidine derivatives. Org. Med. Chem., 2009, 48(2), 273-281.
Popiołek, Ł. Hydrazide-hydrazones as potential antimicrobial agents: Overview of the literature since 2010. Med. Chem. Res., 2017, 26(2), 287-301.
Chandrasekhar, K.B.; Rajasekhar, N. Synthesis, characterization and antibacterial evaluation of some novel hydrazone derivatives of 3-Chloro-4-Hydroxy-Benzoic acid. Ind. J. Chem. Sect. B Org. Med. Chem., 2015, 54B(7), 902-907.
Sonawane, S.J.; Kalhapure, R.S.; Govender, T. Hydrazone linkages in PH responsive drug delivery systems. Eur. J. Pharm. Sci., 2017, 99, 45-65.
Patil, B.R.; Machakanur, S.S.; Hunoor, R.S.; Badiger, D.S.; Gudasi, K.B.; Bligh, A.S.W. Synthesis and anti-cancer evaluation of cyclotriphosphazene hydrazone derivatives. Der. Pharm Chem., 2011, 3(4), 377-388.
Gavara, L.; Boisse, T.; Hénichart, J.P.; Daïch, A.; Rigo, B.; Gautret, P. Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in friedländer reaction. Tetrahedron, 2010, 66(38), 7544-7561.
Koneman, E.W.; Winn, W.C.; Allen, S.D.; Janda, W.M.; Procop, G.W.; Schrenckenberger, P.C.; Woods, G.L. Koneman’s color atlas and textbook of diagnostic microbiology. J. Clin. Microbiol., 2009.
Pfaller, M.A.; Haturvedi, V.; Espinel-Ingroff, A.; Ghannoum, M.A.; Gosey, L.L.; Odds, F.C.; Rex, J.H.; Rinaldi, M.G.; Sheehan, D.J.; Walsh, T.J.; Warnock, D.W. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard, 2nd ed; Serving the World’s Medical Science Community Through Voluntary Consensus, 2002.
Patel, J.B.; Cockerill, R.F.; Bradford, A.P.; Eliopoulos, M.G.; Hindler, A.J.; Jenkinsm, G.S.; Lewis, S.J.; Limbago, B.; Miller, A.L.; Nicolau, P.D.; Pwell, M.; Swenson, M.J.; Traczewski, M.M.; Turnidge, J.D. M07-A10: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard; 10th Ed.; CLSI (Clinical Lab. Stand. Institute): Vol. 35,, 2015.
Rex, J.H.; Barbara, D.A.; Andes, D.; Beth, A.S.; Steven, D.B.; Chaturveli, V.; Espinel-Ingroff, A. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standart-Second; Clinical Lab. Stand. Institute: Vol. 28 2008.
Sahin, E.; Baycu, C.; Koparal, A.T.; Donmez, D.B.; Bektur, E. Resveratrol reduces IL-6 and VEGF secretion from co-cultured A549 lung cancer cells and adipose-derived mesenchymal stem cells. Tumour Biol., 2016, 37, 7573-7582.
De Oliveira, D.B.; Gaudio, A.C. BuildQSAR: A new computer program for QSAR analysis, Quant. Struct. Relationships, 2001, 19(6), 599-601.
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
Gfeller, D.; Michielin, O.; Zoete, V. Shaping the interaction landscape of bioactive molecules. Bioinformatics, 2013, 29(23), 3073-3079.
Rosselli, S.; Bruno, M.; Raimondo, F.M.; Spadaro, V.; Varol, M.; Koparal, A.T.; Maggio, A. Cytotoxic effect of eudesmanolides isolated from flowers of Tanacetum vulgare ssp. Siculum. Molecules, 2012, 17, 8186-8195.
Gomes, A.; Giri, B.; Alam, A.; Mukherjee, S.; Bhattacharjee, P.; Gomes, A. Anticancer activity of a low immunogenic protein toxin (BMP1) from Indian toad (Bufo melanostictus, Schneider) skin extract. Toxicon, 2011, 58(1), 85-92.
Bostancioǧlu, R.B.; Peksen, C.; Genc, H.; Gürbüz, M.; Karel, F.B.; Koparal, A.S.; Dogan, A.; Kose, N.; Koparal, A.T. Analyses of the modulatory effects of antibacterial silver doped calcium phosphate-based ceramic nano-powder on proliferation, survival, and angiogenic capacity of different mammalian cells in vitro. Biomed. Mater., 2015, 10(4)045024
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20(4), 269-276.
Ertl, P. Calculation of molecular properties and bioactivity score©. Molinspiration Cheminformatics, 2002.
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 46(1-3), 3-26.
Mittal, B.; Tulsyan, S.; Kumar, S.; Mittal, R.D.; Agarwal, G. Cytochrome P450 in cancer susceptibility and treatment. Adv. Clin. Chem., 2015, 71, 77-139.
Tervasmäki, A.; Winqvist, R.; Jukkola-Vuorinen, A.; Pylkäs, K. Recurrent CYP2C19 deletion allele is associated with triple-negative breast cancer. BMC Cancer, 2014, 14, 902.
Husain, A.; Ahmad, A.; Khan, S.A.; Asif, M.; Bhutani, R.; Al-Abbasi, F.A. Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents. Saudi Pharm. J., 2016, 24, 104-114.
Manna, S.; Bostner, J.; Sun, Y.; Miller, L.D.; Alayev, A.; Schwartz, N.S.; Lager, E.; Fornander, T.; Nordenskjöld, B.; Yu, J.J.; Stål, O.; Holz, M.K. ERRα is a marker of tamoxifen response and survival in triple-negative breast cancer. Clin. Cancer Res., 2016, 22, 1421-1431.
Fish, L.; Pencheva, N.; Goodarzi, H.; Tran, H.; Yoshida, M.; Tavazoie, S.F. Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts. Genes Dev., 2016, 30(4), 386-398.
Savai, R.; Pullamsetti, S.S.; Banat, G-A.; Weissmann, N.; Ghofrani, H.A.; Grimminger, F.; Schermuly, R.T. Targeting cancer with phosphodiesterase inhibitors. Expert Opin. Investig. Drugs, 2010, 19, 117-131.
Jun, J.H.; Kumar, V.; Dexheimer, T.S.; Wedlich, I.; Nicklaus, M.C.; Pommier, Y.; Malhotra, S.V. Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition activity of novel piperidinyl sulfamides. Eur. J. Pharm. Sci., 2018, 111, 337-348.

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Article Details

Year: 2019
Page: [1658 - 1669]
Pages: 12
DOI: 10.2174/1871520619666190318125824
Price: $58

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