Synthesis, Spectral, Anti-Liver Cancer and Free Radical Scavenging Activity of New Azabicyclic Thienoyl Hydrazone Derivatives


To exploit the potential biological activities of azabicyclic based, seven 2r, 4c-diaryl-3-azabicyclo [3.3.1] nonan-9-one-2’-thienoyl hydrazone were synthesized. The structural elucidation and stereochemistry of these compound assigned by FT-IR, 1H, 13C and 2D NMR spectral data. The Structural Activity Relationship (SAR) of the target compounds were examined for their in vitro anti-proliferative, antioxidant and antimicrobial activities. The initial screen was treated against human liver cancer cell lines (HepG2) with IC50 values determined by MTT assay. Fluoro substitution at para position of phenyl ring compound 12 showed more antiproliferative activity against HepG2 at half maximum inhibitory concentration (IC50 = 3.76 μg/mL) than other target hydrazones. The mechanism of the antitumor action of active compound 12 was investigated through Hoechst stain 33342 analyses. It indicated that the compound inhibited HepG2 cancer cells proliferation by triggering apoptotic cell death. The Free radical scavenging activity of all synthesized compounds were evaluated with , and radicals. The compounds 11 (IC50 rang 3.78 - 4.31 μg/mL) and 15 (IC50 rang 4.61 - 5.16 μg/mL) were exhibited higher free radical scavenging activity than standard BHT drug. Besides, all the target compounds were screened for their in vitro antibacterial and antifungal activity against a spectrum of microbial organisms by using twofold dilution method. These studies proved that halogen substituted compounds 12, 13 and 14 were showed excellent inhibitory potency at lowest minimum inhibitory concentration (MIC) range of 6.25 - 25.5 μg/mL. Nevertheless, multiple mechanisms regulating the antioxidant and anticancer effects of the hybrid molecules need to be further investigations.

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Manimaran, M. , Ganapathi, A. and Balasankar, T. (2015) Synthesis, Spectral, Anti-Liver Cancer and Free Radical Scavenging Activity of New Azabicyclic Thienoyl Hydrazone Derivatives. Open Journal of Medicinal Chemistry, 5, 33-47. doi: 10.4236/ojmc.2015.53004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] (2013) Cancer. Fact Sheet No. 297, World Health Organization, Geneva.
[2] Poljsak, B., Suput, D. and Milisav, I. (2013) Achieving the Balance between ROS and Antioxidants: When to Use the Synthetic Antioxidants. Oxidative Medicine and Cellular Longevity, 2013, Article ID: 956792.
[3] Valko, M., Leibfritz, D., Moncol, J., et al. (2007) Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease. International Journal of Biochemistry & Cell Biology, 39, 44-84.
[4] Kasai, H. and Kawai, K. (2006) Oxidative DNA Damage: Mechanisms and Significance in Health and Disease. Antioxidants & Redox Signaling, 8, 981-983.
[5] Jayaraman, P. and Avila, S. (1981) Chemistry of 3-Azabicyclo [3.3.1] Nonanes. Chemical Reviews, 81, 149-174.
[6] Hardick, D.I., Balagbrough, I.S., Cooper, G., Potter, B.V.L., Critchley, T. and Wonnacott, S. (1996) Nudicauline and Elatine as Potent Norditerpenoid Ligands at Rat Neuronal a-Bungarotoxin Binding Sites: Importance of the 2-(Methyl- succinimido)benzoyl Moiety for Neuronal Nicotinic Acetylcholine Receptor Binding. Journal of Medicinal Chemistry, 39, 4860-4866.
[7] Barker, D., Lin, D.H.S., Crland, J.E., Chu, C.P.Y., Chebib, M., Brimble, M.A., Savage, C.P. and Mclead, M.D. (2005) Methyllycaconitine Analogues Have Mixed Antagonist Effects at Nicotinic Acetylcholine Receptors. Bioorganic & Medicinal Chemistry, 13, 4565-4575.
[8] Sankar, C. and Pandiarajan, K. (2010) Synthesis and Anti-Tubercular and Antimicrobial Activities of Some 2r, 4c-diaryl- 3-azabicyclo[3.3.1] Nonan-9-One N-Isonicotinoylhydrazone Derivatives. European Journal of Medicinal Chemistry, 46, 5480-5485.
[9] Ramachandran, R., Rani, M. and Kabilan, S. (2010) Synthesis, Structure and Conformational Analysis of 2,4-Diaryl-3- Azabicyclo[3.3.1]nonan-9-One Thiosemicarbazones and Semicarbazones. Journal of Molecular Structure, 970, 42-50.
[10] Khaledi, H., Alhadi, A.A., Yehye, W.A., Ali, H.M., Abdulla, M.A. and Hassandarvish, P. (2011) Antioxidant, Cytotoxic Activities, and Structure-Activity Relationship of Gallic Acid-Based Indole Derivatives. Archiv der Pharmazie, 344, 703-709.
[11] Lee, C.Y., Sharma, A., Uzarski, R.L., Cheong, J.E., Xu, H., Held, R.A., Upadhaya, S.K. and Nelson, J.L. (2011) Potent Antioxidant Dendrimers Lacking Pro-Oxidant Activity. Free Radical Biology and Medicine, 50, 918-925.
[12] Chitra, S., Devanathan, D. and Pandiarajan, K. (2010) Synthesis and in Vitro Microbiological Evaluation of Novel 4-Aryl-5-Isopropoxycarbonyl-6-Methyl-3,4-Dihydropyrimidinones. European Journal of Medicinal Chemistry, 45, 367-371.
[13] Rossi, C., Figini, A. and Corpi, A. (1968) Antiarrhythmic Action of Certain 1,5-Diphenyl-Bispidin Derivatives. Annali dell’Istituto Superiore di Sanità, 4, 333. (1969) Chemical Abstracts Service, 70, 85997s.
[14] Chivarelli, S., Delcarmine, R. and Michalek, H. (1972) Effect of Some Antiarrhythmic 1,5-Diphenyl-Bispidine Derivatives on in Vitro Oxygen Uptake and Glucose Utilization of Rat Heart Muscle. Annali dell’Istituto Superiore di Sanità, 8, 156. (1973) Chemical Abstracts Service, 78, 24098z.
[15] Binning, F., Friedrich, L., Hofmann, H.P., Kreiskoh, H., Raschack, M. and Muller, C. (1978) Neue Bispidinderivate, verfahren Zu deren Herstellung und Arzneimittel, Welche diese enthalten. German Patent No. 2726571. (1979) Chemical Abstracts Service, 90, 121568h.
[16] a) Ganellin, C.R. and Spickett, R.G.W. (1965) Compounds Affecting the Central Nervous System. I. 4-Piperidones and Related Compounds. Journal of Medicinal Chemistry, 8, 619-625.
b) El-Subbagh, H.I., Abu-Zaid, S.M., Mahran, M.A., Badria, F.A. and Al-obaid, A.M. (2000) Synthesis and Biological Evaluation of Certain α,β-Unsaturated Ketones and Their Corresponding Fused Pyridines as Antiviral and Cytotoxic Agents. Journal of Medicinal Chemistry, 43, 2915-2921.
[17] Olayinka, O.A., Craig, A.O., Obinna, C.N. and David, A.A. (2010) Microwave Assisted Synthesis and Antimicrobial Activity of 2-Quinoxalinone-3-Hydrazone Derivatives. Bioorganic & Medicinal Chemistry, 18, 214-221.
[18] Fang, V.S., Minkin, C. and Goldhaber, P. (1971) 2-Thiophenecarboxylic Acid: Inhibitor of Bone Resorption in Tissue Culture. Science, 172, 163-165.
[19] Pratt, J.W. (2003) In: Wiley-VCH, Ed., Ullmann’s Encyclopedia of Industrial Chemistry, Vol. 36, Wiley-VCH, Weinheim, 653.
[20] Baliah, V. and Jeyaraman, R. (1971) Synthesis of Some 3-Azabicyclo[3.3.1]Nonan-9-One. Indian Journal of Chemistry, 9, 1020-2022.
[21] Blois, M.S. (1958) Antioxidant Determinations by the Use of a Stable Free Radical. Nature, 26, 1199-1200.
[22] Ren, J.Y., Zhao, M.M., Shi, J., Wang, J.S., Jiang, Y.M., Cui, C., et al. (2008) Purification and Identification of Antioxidant Peptides from Grass Carp Muscle Hydrolysates by Consecutive Chromatography and Electrospray Ionization-Mass Spectrometry. Food Chemistry, 108, 727-736.
[23] Garratt, C.J. (1964) Effect of Iodination on the Biological Activity of Insulin. Nature, 201, 1324-1325.
[24] Mosmann, T. (1983) Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. Journal of Immunological Methods, 65, 55-63.
[25] Standar, A., Marais, S., Stivaktas, V., Vorster, C., Albrecht, C., Lottering, M.-L. and Joubert, A.M. (2009) In Vitro Effects of Sutherlandia frutescens Water Extracts on Cell Numbers, Morphology, Cell Cycle Progression and Cell Death in a Tumorigenic and a Non-Tumorigenic Epithelial Breast Cell Line. Journal of Ethnopharmacology, 124, 45-60.
[26] Dhar, M.H., Dhar, M.M., Dhawan, B.N., Mahrora, B.N. and Ray, C. (1968) Screening of Indian Plants for Biological Activity: I. Indian Journal of Experimental Biology, 6, 232-247.
[27] Sylvestre, S. and Pandiarajan, K. (2011) NMR Spectral Study of Some2r,6c-Diarylpiperidine-4-One (3’-Hydroxy-2’- Napthoyl)Hydrazones with Special Reference to γ-Syn Effect. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 78, 153-159.
[28] Gladii, Y.P., Omarov, T.T. and Buranbaev, M.Z. (1993) X-Ray Diffraction Study of 2,4-Diphenyl-9-Ethynyl-3-Aza- bicyclo-[3.3.1]Nonan-9-Ol. Journal of Structural Chemistry, 34, 336-338.
[29] WHO (World Health Organization) (2008) World Cancer Report. 1-26.
[30] Bray, F., Jemal, A., Grey, N., Ferlayand, J. and Forman, D. (2012) Global Cancer Transitions According to the Human Development Index (2008-2030): A Population-Based Study. Lancet Oncology, 13, 790-801.
[31] Hosono, S., Lee, C.S., Chou, M.J., Yang, C.S. and Shih, C.H. (1999) Molecular Analysis of the p53 Alleles in Primary Hepatocellular Carcinomas and Cell Lines. Oncogene, 6, 237-243.
[32] Le Gall, R., Marchand, C. and Rees, J. (2005) Impacts of Antibiotics on in Vitro UVA-Susceptibility of Human Skin Fibroblasts. European Journal of Dermatology, 15, 146-151.
[33] Xaiver, J.J.F., Krishnasamy, K. and Sankar, C. (2012) Synthesis and Antibacterial, Antifungal Activities of Some 2r,4c-Diaryl-3-Azabicyclo[3.3.1]Nonan-9-One-4-Aminobenzoyl Hydrazones. Medicinal Chemistry Research, 21, 345- 350.

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