Synthesis and cholinesterase enzymes inhibition of novel eugenol substituted carbamate derivatives

Yıl 2017, , 335 - 342, 01.06.2017

Fatih Sönmez

https://doi.org/10.16984/saufenbilder.284240

Öz

In this study, 14 novel eugenol derivatives with the carbamate moiety were synthesized and their inhibitory effects on
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 4-allyl-2-methoxyphenyl-(3,4-
dicholorophenyl)carbamate (3f) was found to be the most potent AChE inhibitor with IC50 value of 71.6 µM, and 4-
allyl-2-methoxyphenyl(3-methoxyphenyl)carbamate (3a) exhibited the strongest inhibition against BuChE with IC50
value of 0.58 µM. Additionally, structure-activity relationship were also investigated. 

Anahtar Kelimeler

Eugenol, carbamate, Alzheimer’s disease

Eugenol sübstitüe yeni karbamat türevlerinin sentezi ve kolinesteraz enzimlerinin inhibisyonu

Öz

Bu çalışmada, karbamat grubu içeren 14 yeni eugenol türevleri sentezlenmiş ve bunların asetilkolinesteraz (AChE) ve
bütirilkolinesteraz (BuChE) enzimleri üzerine inhibitör etkileri incelenmiştir. 4-allil-2-metoksifenil-(3,4-
diklorofenil)karbamat (3f) 71.6 µM’lık IC50 değeri ile en iyi AChE inhibitörü olarak belirlenmiştir. 4-allil-2-
metoksifenil(3-metoksifenil)karbamat (3a) 0.58 µM’lık IC50 değeri ile BuChE’ye karşı en güçlü inhibisyonu
sergilemiştir. Ayrıca sentezlenen bileşikler için yapı-aktivite ilişkileri de incelenmiştir.  

Anahtar Kelimeler

Eugenol, Karbamat, Alzheimer hastalığı

Kaynakça

• [1] O. di Pietro, E. Viayna, E. V. Garcia, M. Bartolini, R. Ramon, J. J. Jimenez, M. V. Clos, B. Perez, V. Andrisano, F. J. Luque, R. Lavilla, and D. M. Torrero, “1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies,” Eur. J. Med. Chem., vol. 73, pp. 141-152, Feb. 2014.
• [2] P. M. Ruiz, L. Rubio, E. G. Palomero, I. Dorronsoro, M. M. Millan, R. Valenzuela, P. Usan, C. de Austria, M. Bartolini, V. Andrisano, A. B. Chanal, M. Orozco, F. J. Luque, M. Medina, and A. Martinez, “Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: New disease-modifying agents for alzheimer’s disease,” J. Med. Chem., vol. 48, no. 23, pp. 7223-7233, Oct. 2005.
• [3] M. Ignasik, M. Bajda, N. Guzior, M. Prinz, U. Holzgrabe, and B. Malawska, “Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors,” Arch. Pharm. Chem. Life Sci., vol. 345, no. 7, pp.509-516, Mar. 2012.
• [4] F. C. Meng, F. Mao, W. J. Shan, F. Qin, L. Huang, and X. S. Li, “Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating agents,” Bioorg. Med. Chem. Lett., vol. 22, no. 13, pp. 4462–4466, Jul. 2012.
• [5] S. S. Xie, X. B. Wang, J. Y. Li, L. Yang, and L. Y. Kong, “Design, synthesis and evaluation of novel tacrineecoumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease,” Eur. J. Med. Chem., vol. 64, pp. 540-553, Jun. 2013.
• [6] M. Shidore, J. Machhi, K. Shingala, P. Murumkar, M. K. Sharma, N. Agrawal, A. Tripathi, Z. Parikh, P. Pillai, and M. R. Yadav, “Benzylpiperidine-linked diarylthiazoles as potential anti-alzheimer’s agents: Synthesis and biological evaluation,” J. Med. Chem., vol. 59, no. 12, pp. 5823–5846, Jun. 2016.
• [7] Q. Yu, H. W. Holloway, T. Utsuki, A. Brossi, and N. H. Greig, “Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for alzheimer’s disease,” J. Med. Chem., vol. 42, no. 10, pp. 1855-1861, May 1999.
• [8] Z. P. Wu, X. W. Wu, T. Shen, Y. P. Li, X. Cheng, L. Q. Gu, Z. S. Huang, and L. K. An, “Synthesis and acetylcholinesterase and butyrylcholinesterase inhibitory activities of 7-alkoxyl substituted indolizinoquinoline-5,12-dione derivatives,” Arch. Pharm. Chem. Life Sci., vol. 345, no. 3, pp. 175–184, Oct. 2012.
• [9] N. Chitranshi, S. Gupta, P. K. Tripathi, and P. K. Seth, “New molecular scaffolds for the design of Alzheimer’s acetylcholinesterase inhibitors identified using ligand- and receptor-based virtual screening,” Med. Chem. Res., vol. 22, no. 5, pp. 2328–2345, May 2013.
• [10] C. Guillou, A. Mary, D. Z. Renko, E. Gras, and C. Thal, “Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts,” Bioorg. Med. Chem. Lett., vol. 10, no. 7, pp. 637-639, Apr. 2000.
• [11] H. Göçer, A. Akincioğlu, S. Göksu, İ. Gülçin, and C. T. Supuran, “Carbonic anhydrase and acetylcholinesterase inhibitory effects of carbamates and sulfamoylcarbamates,” J. Enzyme Inhib. Med. Chem., vol. 30, no. 2, pp. 316-320, 2015.
• [12] M. Pohanka, “Acetylcholinesterase inhibitors: a patent review (2008-present),” Expert Opin. Ther. Pat., vol. 22, no. 8, pp. 871-886, Jul. 2012.
• [13] M. L. Bolognesi, M. Bartolini, A. Cavalli, V. Andrisano, M. Rosini, A. Minarini, and C. Melchiorre, “Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues,” J. Med. Chem., vol. 47, no. 24, pp. 5945-5952, Oct. 2004.
• [14] S. Darvesh, K. V. Darvesh, R. S. McDonald, D. Mataija, R. Walsh, S. Mothana, O. Lockridge, and E. Martin, “Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase,” J. Med. Chem., vol. 51, no. 14, pp. 4200–4212, Jun. 2008.
• [15] J. C. Verheijen, K. A. Wiig, S. Du, S. L. Connors, A. N. Martin, J. P. Ferreira, V. I. Slepnev, and U. Kochendörfer, “Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition,” Bioorg. Med. Chem. Lett., vol. 19, no. 12, pp. 3243–3246, Jun. 2009.
• [16] M. J. Balunas, and A. D. Kinghorn, “Drug discovery from medicinal plants,” Life Sci., vol. 78, no. 5, pp. 431–441, Dec. 2005.
• [17] M. Jukic, O. Politeo, M. Maksimovic, M. Milos, and M. Milos, “In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone,” Phytother. Res., vol. 21, no. 3, pp. 259–261, Mar. 2007.
• [18] J. Mastelic, I. Jerkovic, I. Blazevic, M. P. Blazi, S. Borovic, I. I. Bace, V. Smrecki, N. Zarkovic, K. B. Kostic, D. V. Topic, and N. Muller, “Comparative study on the antioxidant and biological activities of carvacrol, thymol, and eugenol derivatives,” J. Agric. Food Chem., vol. 56, no. 11, pp. 3989-3996, May 2008.
• [19] H. Sadeghian, S. M. Seyedi, M. R. Saberi, Z. Arghiani, and M. Riazi, “Design and synthesis of eugenol derivatives, as potent 15-lipoxygenase inhibitors,” Bioorg. Med. Chem., vol. 16, no. 2, pp. 890-901, Jan. 2008.
• [20] J. D. Barbosa, V. B. Silva, P. B. Alves, G. Gumina, R. L. Santos, D. P. Sousa, and S. C. Cavalcanti, “Structure–activity relationships of eugenol derivatives against Aedes aegypti (Diptera: Culicidae) larvae,” Pest Manag. Sci., vol. 68, no. 11, pp. 1478-1483, Jun. 2012.
• [21] N. Chaibakhsh, M. Basri, S. H. M. Anuar, M. B. A. Rahman, and M. Rezayee, “Optimization of enzymatic synthesis of eugenol ester using statistical approaches,” Biocatal. Agric. Biotechnol., vol. 1, no. 3, pp. 226-231, Jul. 2012.
• [22] G. D. Yadav, and A. R. Yadav, “Insight into esterification of eugenol to eugenol benzoate using a solid super acidic modified zirconia catalyst UDCaT-5,” Chem. Eng. J., vol. 192, pp. 146-155, Jun. 2012.
• [23] S. Dohi, M. Terasaki, and M. Makino, “Acetylcholinesterase inhibitory activity and chemical composition of commercial essential oils,” J. Agric. Food Chem., vol. 57, no. 10, pp. 4313-4318, Apr. 2009.
• [24] I. Orhan, M. Kartal, Y. Kan, and B. Şener, “Activity of essential oils and individual components against acetyl- and butyrylcholinesterase,” Z. Naturforsch. C, vol. 63, no. 7-8, pp. 547-553, Aug. 2008.
• [25] G. L. Ellman, K. D. Courtney, V. Andres, and R. M. Featherstone, “A new and rapid colorimetric determination of acetylcholinesterase activity,” Biochem. Pharmacol., vol. 7, no. 2, pp. 88–95, Jul. 1961.