Synthesis and biologic activity of bis and mono nitrophenyl substituted ferrocene and their interaction with O2/O2- redox couple using cyclic voltammetry

S. Benabdesselam, O. Rahim


Abstract: In this work, 3-nitrophenylferrocene (3-NPF) and bis-3-nitrophenylferrocene (bis-3-NPF) were synthesized through the arylation of ferrocene by diazotasing of 3-nitroaniline by sodium nitrite in the presence of H2SO4 to form meta-nitrobenzendiazonium sulfide. The synthesized compounds were characterized by IR infrared and NMR magnetic resonance spectroscopy (1H, 13C and DEPT). The superoxide scavenging effect was assessed by electrochemical assay; cyclic voltammetry, the DPPH scavenging assay and total antioxidant capacity were assessed using spectrophotometric assay. In this paper, the antioxidant capacity index (IC50) towards supreroxide anion radical, DPPH radical and TAC were determined, we found that the IC50 of compounds against superoxide ranged from 1.212 to 2.709mg/ml, the lowest value of IC50 was detected in bis-3-NPF, the DPPH radical inhibition capacities are in the order of ascorbic acid˃α-Tocopherol˃bis-3-NPF˃3-NPF˃ with IC50 respectively of 0.0063mg/ml, 0.0134mg/ml, 0.773mg/ml and 1. 44mg/ml and the maximum Mo(VI)  reducing activity was observed at high concentrations (0.8 mg/ml), the TAC of the compounds was found to be in the following order: Bis-3-NPF ˃ 3-NPF. The antioxidant activity coefficients (Ka), the interaction coefficients (Kb) and the binding free energy of these two ferrocene derivatives towards the superoxide radical were determined using the values of the intensities of the anodic currents from the cyclic voltammograms of the O2/O2- couple.

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Mao-Lin, H.; Abbasi-Azad, M. ; Habibi,B. ; Rouhani, F. ; Moghanni, H. ; Olyaei, B. ; Liu, K.G. ; Morsali, A .Electrochemical application of ferrocene-based coordination polymers. ChemPlusChem 85 (2020) 2397-2418.

Aslam Ertas, N. ; Kavak, E. ; Salman, F.; Hilal Celik Kazici, H.C.; Kivrak, H.; Arif Kivrak. Synthesis of ferrocene based naphtoquinones and its application as novel non-enzymatic hydrogen peroxide. Electroanalysis 32 (2020) 1178-1185.

Liang, J.; Gao, X.; Guo, B.; Ding, Y.; Yan, J.; Guo, Z.; Cm Tse, E.; Liu, J. Ferrocne –based Metal- organic frame work nanosheets as a robust oxygen evolution catalyst. Angewandte chemie 133(2021) 12880-12884

Fischer, E.O.; Jira, R. Journal of Organometalic Chemistry 7(2001) 637–639.

Sarkar, T.; Banarjee, S.; Mukherjee, S.; Hussain, A. Mitochondrial selectivity and remarkable photocytotoxicity of a ferrocenyl neodymium (II) complex of terpyridine and curcumin in cancer cells. Dalton transactions 45(2016) 6424–6424.

Vera, J.; Gao, L.M.; Santana, A.; Mattab, J.; Melendez, E. Vectorized ferrocenes with estrogens and vitamin D2: synthesis, cytotoxic activity and docking studies. The Royal Society of Chemistry 40 (2011) 9557–9565.

Károlyi, B.I.; Bősze, S.; Orbán, E.; Sohár, P.; Drahos, L.; Gál, E.; Csámpai, A. Acylated mono-, bis- and tris- Cinchona-Based Amines Containing Ferrocene or Organic Residues: Synthesis, Structure and in Vitro Antitumor Activity on Selected Human Cancer Cell Lines. Molecules 17(2012) 2316-2329

Iacovino, R.; Caso, J.V.; Rapuano, F.; Russo, A.; Isidori, M.; Lavorgna, M.; Malgieri, G.; Isernia, C. Physicochemical Characterization and Cytotoxic Activity Evaluation of Hydroxymethyl ferrocene: β Cyclodextrin Inclusion Complex. Molecules 17 (2012) 6056-607

Gadhachanda, V.R.; Eastman, K.J.; Wang, Q.; Avinash, S.; Phadke, A.S.; Patel , D.; Yang, W.; Marlor, C.W.; Deshpande, M.; Huang, M , Wiles, J.A. Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity. Bioorganic and medicinal chemistry letters 28(2018) 3463-3471

Tiwari, K.N.; J.P. Monserrat, J.P.; Hequet, A.; Ganem-Elbaz, C.; Cresteil, T.; Jaouen, G.; Vessières, A.; Hillard, E.A.; Jolivalt. C. In vitro inhibitory properties of ferrocene substituted chalcones and aurones on bacterial and human cell cultures. Dalton Transactions 41(2012) 6451–6457

Liu, Y.T.; Lian, G.D.; Yin, D-W.; Su, B-J. Synthesis and antimicrobial activity of some novel ferrocene-based Schiff bases containing a ferrocene unit. Research on Chemical Intermediates 38(2012) 1043–1053.

García-Barrantes, P.M.; Lamoureux, V.V.; Pérez, A.L.; García-Sánchez, R.N.; Martínez, A.R.; San Feliciano, A. Synthesis and biological evaluation of novel ferroceneenaphthoquinones as antiplasmodial agent. European Journal of Medicinal Chemistry 70 (2013) 548-557.

Yavuz, S.; Yildirim, H. Ferrocene Derivatives Carrying Urea, Thiourea, and Sulfonamide Moieties, Synthesis and Evaluation of Antibacterial and Antifungal Activities. Journal of Chemistry 86(2014) 759-768.

Xi, G-L.; Liu, Z-Q. Solvent-free Povarov reaction for synthesizing ferrocenyl quinolines: Antioxidant abilities deriving from ferrocene moiety. European Journal of Medicinal Chemistry 86(2014) 759-768

Nabi, G.; Liu, Z-Q. Radical-scavenging properties of ferrocenyl chalcones. Bioorganic and Medicinal Chemistry Letters 21 (2011) 944–946.

Azadar Hussain, R.; Badshash, A.; Sohail, M.; Lal, B.; Altaf, AA. Synthesis, chemical characterization, DNA interaction and antioxidant studies of ortho, meta and para fluoro substituted ferrocene incorporated selenoureas. Inorganica Chimica Acta 402(2013) 133–139.

Benabdesselam, S.; Lanez, T. Evaluation of total antioxidant capacity and free radicals scavenging of 2 and 4- Nitrophenylferrocene by electrochemical and chemical assays. Journal of Chemical and Pharmaceutical Research 7(2015) 825-831

Zhang, J.; Liu, R. Synthesis, Characterization and Antioxidant Activity of Ferrocenylhydrazones. Journal of the Chemical Society of Pakistan 33 (2011).

Asghar, F.; Badshah, A.; Shah, A.; Khawar Rauf, M.; Irshad Ali, M.; Nawaz Tahir, M.; Nosheen, E.; Ur-Rehman, Z.; Qureshi, R. Synthesis, characterization and DNA binding studies of organoantimony(V) ferrocenyl benzoates. Journal of Organometallic Chemistry 717(2012) 1-8

Zaheer, M.; Shah, A.; Akhter, Z.; Qureshi, R.; Mirza, B.; M. Tauseef, M.; Bolte, M. Synthesis, characterization, electrochemistry and evaluation of biological activities of some ferrocenyl Schiff bases. Applied organometallic chemistry 25(2011) 61–69.

Rezaire, A. Activité anti-oxydante et caractérisation phénolique du fruit de palmier amazonien Oenocarpus bataua (patawa). PhD thesis in phytochemistry. Antilles et de la Guyane University.( 2012).

Bahorun, T.; Soobrattee, M.A.; Luximon-Ramma, V.; Aruoma, OI. Free Radicals and Antioxidants in Cardiovascular Health and Disease. Internet Journal of Medical Update 1(2006).

Benabdesselam, S.; Izza, H.; Lanez, T.; Guechi, EK. Synthesis, antioxidant and antibacterial activities of 3-nitrophenylferrocene. IOP conference series: IOP Conf. Series: Materials Science and Engineering 323 (2018) 012007.

Brand-Williams, W.; Cuvelier, M.E.; Berset, C. Use of a Free Radical Method to Evaluate Antioxidant Activity. LWT-Food science and technology 28(1995) 25-30.

Behrendorff, J.B.; Vickers, C.E.; Chrysanthopoulos, P.; Nielsen, L.K. 2, 2-Diphenyl-1-picrylhydrazyl as a screening tool for recombinant monoterpene biosynthesis. Microbial Cell Factories 12(2013) 1475-2859.

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. Analytical Biochemistry 269 (1999) 337-341.

Le Bourvellec, C.; Hauchard, D.; Darchen, A.; Burgot, J-L.; Abasq, M-L. Validation of a new method using the reactivity of electrogenerated superoxide radical in the antioxidant capacity determination of flavonoids. Talanta 75 (2008) 1098–1103.

Safeer, A.; Shakeel, F. Antioxidant Activity Coefficient, Mechanism, and Kinetics of Different Derivatives of Flavones and Flavanones towards Superoxide Radical. Czech Journal of Food Sciences 30 (2012) 153–163

Safeer, A.; Shakeel, F. Voltammetric determination of antioxidant character in Berberis lycium Royel, Zanthoxylum armatum and Morus nigra Linn plants. Pakistan Journal of Pharmaceutical Sciences 25(2012) 501-507

Atkins, P, Atkins’s physical chemistry. Oxford University Press, Oxford (1986) 263-265

Patrick, G.L.; Winter, H.D.; Langenaeker, W.; Tollenaere, J.P. Computational Medicinal Chemistry for Drug Discovery, Marcel Dekker, New York (1995).

Kier, L.B. Molecular Orbital Theory in Drug Research, Academic Press, New York, NY, USA (1981).

Sebaa, Z.; Tchouar, N.; Belaidi, S.; Salah, T.; Belkhiri, L. Computational exploration in the electronic structure property/activity relationships and multiparameter optimization of 1,2,5-thiadiazole derivatives. Quantum Matter 6 (2017) 1-7.

Pajouhesh, H. ; Lenz, G.R. Medicinal Chemical Properties of Successful Central Nervous System Drugs. NeuroRx 2(2005)1545-5351

Kerns, E.H.; Di, L. Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization, Academic Press, USA, (2008).

Douadi, K.; Chafaa, S.; Douadi, T.; Al-Noaimi, M.; Kaabi, I. Azoimine quinoline derivatives : synthesis, Classical and electrochemical evaluation of antioxidant, anti-inflammatory, antimicrobial activities and the DNA /BSA binding. Journal of Molecular Structure 1217 (2020) 1283052

Xi, G.L.; Liu, Z-Q. Solvent-free Povarov reaction for synthesizing ferrocenyl quinolines: Antioxidant abilities deriving from ferrocene moiety. European Journal of Medicinal Chemistry 86(2014) 759-768.

Nabi,G.; Liu,Z-Q. Radical-scavenging properties of ferrocenyl chalcones. Bioorganic and Medicinal Chemistry Letters 21(2011) 944–946

Dureja, J.; Chadha, R.; Karan, M.; Jindal, A.; Chadha, K. Binding studies of trans-resveratrol with superoxide dismutase (SOD1) : Docking assessment and Thermoanalysis. Journal of Pharmaceutical and Biopharmaceutical Research 1(2019) 21-27.

Hashemi, S.A; Karami, M.; Bathaie, S.Z. Saffron carotenoids change the superoxide dismutase activity in breast cancer: In vivo; in vitro and in silico studies. International journal of biological macromolecules 158(2020) 845-853.

Benabdesselam, S. ; Rahim, O. Scavenging Potential of Ascorbic Acid, Gallic Acid and α-Tocopherol Towards Electrochemically Generated Superoxide Anion Radical And Evaluation of Their Interaction Using Cyclic Voltammetry. Heterocyclic Letters 11(2021) 521-532.

Benabdesselam, S.; Rahim, O. Synthesis, Antioxidant Activity of 2-Ferrocenyl aniline, Bis-2-Ferrocenylaniline and some Binding Parameters Towards Superoxide Anion Radical. Heterocyclic Letters 11(2021) 359-370.


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