Inhibitory effects of the chalcones towards carbonic anhydrase I, II and acetylcholinesterase enzymes

Year 2020, , 1138 - 1146, 31.12.2020

Mehtap Tuğrak , Cem Yamalı , Halise İnci Gül , Yeliz Demir

https://doi.org/10.18185/erzifbed.748798

Cited By: 2

Abstract

Chalcones are known as versatile, innovative and bioactive chemical scaffolds in drug development studies. In this study, a series of poly-methoxylated chalcones (1-8) were synthesized by Claisen-Schmidt condensation under the basic condition and their carbonic anhydrase (CA) I/II and acetylcholinesterase (AChE) inhibitory effects were firstly evaluated in this study. CA isoenzymes I and II were inhibited in nanomolar concentration with Ki values of 8.75±0.64 - 37.64±2.38 nM (hCA I) and 11.47±3.31- 45.97±4.67 nM (hCA II). The compounds inhibited the AChE enzyme in the range of 34.14±20.79 - 53.65±13.25 nM. The compounds 1, 3 and 5 were the best inhibitors against hCA I, hCA II, and AChE, respectively. The bioassay results showed that the compounds can be considered as the main frame to design novel chalcone-based enzyme inhibitors. 

Keywords

enzyme inhibitor, acetylcholinesterase, Chalcone

Şalkonların karbonik anhidraz I, II ve asetilkolinesteraz enzimlerine karşı inhibisyon etkileri

Abstract

Şalkonlar ilaç geliştirme çalışmalarında kullanışlı, yenilikçi ve biyoaktif kimyasal yapı iskeletleri olarak bilinirler. Bu çalışmada, bir dizi poli-metoksillenmiş şalkonlar (1-8) bazik koşul altında Claisen-Schmidt kondansasyonu ile sentezlendi ve karbonik anhidraz (CA) I / II ve asetilkolinesteraz (AChE) inhibitör etkileri ilk olarak bu çalışmada değerlendirildi. CA izoenzimleri olan I ve II, 8.75 ± 0.64 - 37.64 ± 2.38 nM (hCA I) ve 11.47 ± 3.31- 45.97 ± 4.67 nM (hCA II) Ki değerleri ile nanomolar konsantrasyonda inhibe edildi. Bileşikler, AChE enzimini 34.14 ± 20.79 - 53.65 ± 13.25 nM aralığında inhibe etti. Bileşik 1, 3 ve 5, sırasıyla hCA I, hCA II ve AChE'ye karşı en güçlü inhibitörlerdir. Biyolojik aktivite sonuçları, bileşiklerin yeni şalkon bazlı enzim inhibitörleri tasarlamak için ana yapı olarak kabul edilebildiğini gösterdi.

Chalcones are known as versatile, innovative and bioactive chemical scaffolds in drug development studies. In this study, a series of poly-methoxylated chalcones (1-8) were synthesized by Claisen-Schmidt condensation under the basic condition and their carbonic anhydrase (CA) I/II and acetylcholinesterase (AChE) inhibitory effects were firstly evaluated in this study. CA isoenzymes I and II were inhibited in nanomolar concentration with Ki values of 8.75±0.64 - 37.64±2.38 nM (hCA I) and 11.47±3.31- 45.97±4.67 nM (hCA II). The compounds inhibited the AChE enzyme in the range of 34.14±20.79 - 53.65±13.25 nM. The compounds 1, 3 and 5 were the best inhibitors against hCA I, hCA II, and AChE, respectively. The bioassay results showed that the compounds can be considered as the main frame to design novel chalcone-based enzyme inhibitors.

Keywords

chalcone, carbonic anhydrase, acetylcholine esterase, enzyme inhibitor

References

• Alpan, A.S., Sarıkaya, G., Coban, G., Parlar, S., Armagan, G., Alptuzun, V. 2017. ‘’Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study’’. Arch Pharm (Weinheim), 350(7), e1600351.
• Burmaoglu, S., Yilmaz, A.O., Polat, M.F., Kaya, R., Gulcin, I., Algul, O. 2019. ‘’Synthesis and Biological Evaluation of Novel Tris-Chalcones as Potent Carbonic Anhydrase, Acetylcholinesterase, Butyrylcholinesterase and Alpha-Glycosidase İnhibitors’’. Bioorg Chem, 85, 191-197.
• Ellman, G.L., Courtney, K.D., Andres, V., Jr., Feather-Stone, R.M. 1961. ‘’A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity’’. Biochem Pharmacol, 7, 88-95.
• Gomes, M.N., Muratov, E.N., Pereira, M., Peixoto, J.C., Rosseto, L.P., Cravo, P.V.L., Andrade, C.H., Neves, B.J. 2017. ‘’Chalcone Derivatives: Promising Starting Points for Drug Design’’. Molecules, 22(8), E1210
• Gul, H.I., Yamali, C., Bulbuller, M., Kirmizibayrak, P.B., Gul, M., Angeli, A., Bua, S., Supuran, C.T. 2018a. ‘’Anticancer Effects of New Dibenzenesulfonamides by Inducing Apoptosis and Autophagy Pathways and Their Carbonic Anhydrase İnhibitory Effects on hCA I, hCA II, hCA IX, hCA XII Isoenzymes’’. Bioorg Chem, 78, 290-297.
• Gul, H.I., Yamali, C., Sakagami, H., Angeli, A., Leitans, J., Kazaks, A., Tars, K., Ozgun, D.O., Supuran, C.T. 2018b. ‘’New Anticancer Drug Candidates Sulfonamides as Selective hCA IX or hCA XII Inhibitors’’. Bioorg Chem, 77, 411-419.
• Li, Y., Qiang, X., Luo, L., Yang, X., Xiao, G., Zheng, Y., Cao, Z., Sang, Z., Su, F., Deng, Y. 2017. ‘’Multitarget Drug Design Strategy Against Alzheimer's Disease: Homoisoflavonoid Mannich Base Derivatives Serve As Acetylcholinesterase and Monoamine Oxidase B Dual Inhibitors with Multifunctional Properties’’. Bioorg Med Chem, 25(2), 714-726.
• Mahar, J., Saeed, A., Belfield, K.D., Ali Larik, F., Ali Channar, P., Ali Kazi, M., Abbas, Q., Hassan, M., Raza, H., Seo, S.Y. 2019. ‘’1-(2-Hydroxy-5-((trimethylsilyl)ethynyl)phenyl)ethanone Based Alpha, Beta-Unsaturated Derivatives An Alternate To Non-Sulfonamide Carbonic Anhydrase II Inhibitors, Synthesis Via Sonogashira Coupling, Binding Analysis, Lipinsk's Rule Validation’’. Bioorg Chem, 84, 170-6.
• Ozgun, D.O., Gul, H.I., Yamali, C., Sakagami, H., Gulcin, I., Sukuroglu, M., Supuran, C.T. 2019. ‘’Synthesis and Bioactivities of Pyrazoline Benzensulfonamides as Carbonic Anhydrase and Acetylcholinesterase Inhibitors With Low Cytotoxicity’’. Bioorg Chem, 84, 511-517.
• Ozgun, D.O., Yamali, C., Gul, H.I., Taslimi, P., Gulcin, I., Yanik, T., Supuran, C.T. 2016. ‘’Inhibitory Effects of Isatin Mannich Bases On Carbonic Anhydrases, Acetylcholinesterase, and Butyrylcholinesterase’’. J Enzyme Inhib Med Chem, 31(6), 1498-501.
• Rammohan, A., Reddy, J.S., Sravya, G., Rao, C.N., Zyryanov, G.V. 2020. ‘’Chalcone Synthesis, Properties and Medicinal Applications: A Review’’. Environ Chem Lett, 18, 433-458.
• Supuran, C.T. 2016. ‘’Structure and Function of Carbonic Anhydrases’’. Biochem J, 473(14), 2023-32.
• Supuran, C.T. 2017. ‘’Advances In Structure-Based Drug Discovery of Carbonic Anhydrase Inhibitors’’. Expert Opin Drug Discov, 12(1), 61-88.
• Supuran, C.T. 2018. ‘’Carbonic Anhydrase Inhibitors and Their Potential In A Range of Therapeutic Areas’’. Expert Opin Ther Pat, 28(10), 709-712.
• Supuran, C.T., Vullo, D., Manole, G., Casini, A., Scozzafava, A. 2004. ‘’Designing of Novel Carbonic Anhydrase Inhibitors and Activators’’. Curr Med Chem Cardiovasc Hematol Agents, 2(1), 51-70.
• Supuran, C.T. 2008. ‘’Carbonic anhydrases: Novel Therapeutic Applications for Inhibitors and Activators’’. Nat Rev Drug Discov, 7(2), 168-181.
• Taslimi, P., Sujayev, A., Mamedova, S., Kalin, P., Gulcin, I., Sadeghian, N., Beydemir, S., Kufrevioglu, O.I., Alwasel, S.H., Farzaliyev, V., Mamedov, S. 2017. ‘’Synthesis and Bioactivity of Several New Hetaryl Sulfonamides’’. J Enzym Inhib Med Chem, 32(1), 137-145.
• Temperini, C., Scozzafava, A., Supuran, C.T. 2008. ‘’Carbonic Anhydrase Activation and The Drug Design’’. Curr Pharm Des, 14(7), 708-715.
• Verpoorte, J.A., Mehta, S., Edsall, J.T. 1967. ‘’Esterase Activities of Human Carbonic Anhydrases B and C’’. J Biol Chem, 242(18), 4221-4229.
• Yamali, C., Gul, H.I., Ece, A., Taslimi, P., Gulcin, I. 2018. ‘’Synthesis, Molecular Modeling, and Biological Evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]benzenesulfonamides Toward Acetylcholinesterase, Carbonic Anhydrase I and II Enzymes’’. Chem Biol Drug Des, 91(4), 854-866.
• Yamali, C., Gul, H.I., Kazaz, C., Levent, S., Gulcin, I. 2020. ‘’Synthesis, Structure Elucidation, and In Vitro Pharmacological Evaluation of Novel Polyfluoro Substituted Pyrazoline Type Sulfonamides as Multi-Target Agents for Inhibition of Acetylcholinesterase and Carbonic Anhydrase I and II Enzymes’’. Bioorg Chem, 96, 103627.
• Yamali, C., Gul, H.I., Ozgun, D.O., Sakagami, H., Umemura, N., Kazaz, C., Gul, M. 2017. ‘’ Synthesis and Cytotoxic Activities of Difluoro-Dimethoxy Chalcones’’. Anticancer Agents Med Chem, 17(10), 1426-1433.
• Yamali, C., Gul, H.I., Sakagami, H., Supuran, C.T. 2016. ‘’Synthesis and Bioactivities of Halogen Bearing Phenolic Chalcones and Their Corresponding Bis Mannich Bases’’. J Enzyme Inhib Med Chem, 31(sup4), 125-131.
• Zhang, X., Rakesh, K.P., Bukhari, S.N.A., Balakrishna, M., Manukumar, H.M., Qin, H.L. 20118. ‘’Multi-targetable Chalcone Analogs To Treat Deadly Alzheimer's Disease: Current View and Upcoming Advice’’. Bioorg Chem, 80, 86-93.
• Zengin, M., Genc, H., Taslimi, P., Kestane, A., Guclu, E., Ogutlu, A., Karabay, O., Gulçin, I. 2018. ‘’Novel Thymol Bearing Oxypropanolamine Derivatives As Potent Some Metabolic Enzyme Inhibitors - Their Antidiabetic, Anticholinergic and Antibacterial Potentials’’. Bioorg Chem, 81, 119-126.