Synthesis, Characterization And In-Vitro Studies On Chalcone Based Quinoxaline: Acetylcholinesterase Inhibition Through In-Silico Technique For Alzheimer’s Disease
Main Article Content
Abstract
Inhibition of Acetylcholine esterase (AChE) to prevent the reduction of ACh level in Alzheimer’s disease (AD) patients has been a popular strategy. Therapeutic applications of chalcones and Quinoxalines are becoming the attractive target due to its inherent diverse biological properties in recent times. In this study, virtual library was created containing 15 novel chalcone-quinoxaline hybrid derivatives using CHEMDRAW. Toxicity and ADME properties of those compounds were screened using admetSAR. 2D-QSAR in-silico models were developed to predict the activities of newly designed compounds before a decision is being made whether these compounds should be really synthesized and tested. In addition, docking studies had performed for newly designed compounds using PyRx software. 15 compounds were synthesized and characterized by IR, 1H NMR, 13C NMR and LC-MS. Then all compounds were tested for cell viability in-vitro MTT assay. Among the tested compounds, M2 and M4 were shown to be the most effective against the evaluated cell lines. In-depth, detailed investigations on in-vivo activity may be undertaken. The current study suggests that more research is needed for chalcone merged quinoxaline derivatives developed as a potent lead for Alzheimer's disease.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
References
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E. J.; Fraga, C. A. M. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr. Med. Chem. 2007, 14, 1829−1852.
Zhan, P.; Liu, X. Y. Designed Multiple Ligands: An Emerging Anti-HIV Drug Discovery Paradigm. Curr. Pharm. Des. 2009, 15, 1893−1917.
Zhuang, C. L.; Miao, Z. Y.; Wu, Y. L.; Guo, Z. Z.; Li, J.; Yao, J. Z.; Xing, C. G.; Sheng, C. Q.; Zhang, W. N. Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53-MDM2 Interaction and the NF-kappa B Pathway. J. Med. Chem. 2014, 57, 567−577.
Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CA. Molecular hybridization: a useful tool in the design of new drug prototypes. Current medicinal chemistry. 2007 Jul 1;14(17):1829-52.
Lazar C, Kluczyk A, Kiyota T, Konishi Y. Drug evolution concept in drug design: 1. Hybridization method. Journal of medicinal chemistry. 2004 Dec 30;47(27):6973-82.
Zhou, B.; Xing, C. Diverse Molecular Targets for Chalcones with Varied Bioactivities. Med. Chem. 2015, 5, 388−404.
Batovska, D. I.; Todorova, I. T. Trends in utilization of the pharmacological potential of chalcones. Curr. Clin. Pharmacol. 2010, 5, 1−29.
Sahu, N. K.; Balbhadra, S. S.; Choudhary, J.; Kohli, D. V. Exploring pharmacological significance of chalcone scaffold: a review. Curr. Med. Chem. 2012, 19, 209−225.
Singh, P.; Anand, A.; Kumar, V. Recent developments in biological activities of chalcones: a mini review. Eur. J. Med. Chem. 2014, 85, 758−777.
Karthikeyan, C.; Moorthy, N. S.; Ramasamy, S.; Vanam, U.; Manivannan, E.; Karunagaran, D.; Trivedi, P. Advances in Chalcones with anticancer activities. Recent Pat. Anti-Cancer Drug Discovery 2015, 10, 97−115.
Sebti, S.; Solhy, A.; Smahi, A.; Kossir, A.; Oumimoun, H. Dramatic activity enhancement of natural phosphate catalyst by lithium nitrate. An efficient synthesis of chalcones. Catal. Commun. 2002, 3, 335−339.
Sharma, V.; Kumar, V.; Kumar, P. Heterocyclic Chalcone analogues as potential anticancer agents. Anti-Cancer Agents Med. Chem. 2013, 13, 422−432.
Dimmock, J. R.; Elias, D. W.; Beazely, M. A.; Kandepu, N. M. Bioactivities of chalcones. Curr. Med. Chem. 1999, 6, 1125−1149.
Go, M. L.; Wu, X.; Liu, X. L. Chalcones: an update on cytotoxic and chemoprotective properties. Curr. Med. Chem. 2005, 12, 483−499.
Leon-Gonzalez, A. J.; Acero, N.; Munoz-Mingarro, D.; Navarro, I.; Martin-Cordero, C. Chalcones as Promising Lead Compounds on Cancer Therapy. Curr. Med. Chem. 2015, 22, 3407−3425.
Mahapatra, D. K.; Asati, V.; Bharti, S. K. Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. Eur. J. Med. Chem. 2015, 92, 839−865.
Mahapatra, D. K.; Bharti, S. K.; Asati, V. Chalcone scaffolds as anti-infective agents: structural and molecular target perspectives. Eur. J. Med. Chem. 2015, 101, 496−524.
Mahapatra, D. K.; Bharti, S. K.; Asati, V. Anti-cancer chalcones: Structural and molecular target perspectives. Eur. J. Med. Chem. 2015, 98, 69−114.
Kamal, A.; Kashi Reddy, M.; Viswanath, A. The design and development of imidazothiazole-chalcone derivatives as potential anticancer drugs. Expert Opin. Drug Discovery 2013, 8, 289−304.
Matos, M. J.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L. Potential pharmacological uses of chalcones: a patent review (from June 2011 - 2014). Expert Opin. Ther. Pat. 2015, 25, 351−366.
Das, M.; Manna, K. Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight. J. Toxicol. 2016, 2016, 7651047.
Mahapatra, D. K.; Bharti, S. K. Therapeutic potential of chalcones as cardiovascular agents. Life Sci. 2016, 148, 154−172.
Bukhari, S. N.; Franzblau, S. G.; Jantan, I.; Jasamai, M. Current prospects of synthetic curcumin analogs and chalcone derivatives against mycobacterium tuberculosis. Med. Chem. 2013, 9, 897−903.
Nasir Abbas Bukhari, S. N.; Jasamai, M.; Jantan, I. Synthesis and biological evaluation of chalcone derivatives (mini review). Mini-Rev. Med. Chem. 2012, 12, 1394−1403.
Kontogiorgis, C.; Mantzanidou, M.; Hadjipavlou-Litina, D. Chalcones and their potential role in inflammation. Mini-Rev. Med. Chem. 2008, 8, 1224−1242.
Kumar, D, Kumar M, Kumar A; Singh, S. K. Chalcone and curcumin derivatives: a way ahead for malarial treatment. Mini-Rev. Med. Chem. 2013, 13, 2116−2133.
Shagufta; Ahmad, I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. Med. Chem. Com. 2017, 8, 871–885.
Shagufta; Ahmad, I. Recent insight into the biological activities of the synthetic xanthone derivatives. Eur. J. Med. Chem. 2016, 116, 267–280.
Ahmad, I.; Shagufta. Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of oestrogen-dependent breast cancer. Eur. J. Med. Chem. 2015, 102, 375–386.
Ahmad, I.; Shagufta, S. An important class of organic compounds with diverse biological activities. Int. J. Pharm. Sci. 2015, 7, 19–27.
G.W.H. Chesseman, R.F. C., The Chemistry of Heterocyclic Compounds, Condensed Pyrazines, vol. 35, John Wiley & Sons, Inc., 1979.
A. Patidar, J. M., A. Mobiya, G. Selvam, Int. J. PharmTech Res. 3 (2011) 386e392.
A.s. Association, 2020 Alzheimer’s disease facts and figures, Alzheimers Dement, 2020.
H. Hippius, G. Neundorfer, The discovery of Alzheimer’s disease, Dialog. Clin. Neurosci. 5 (2003) 101–108.
W.V. Graham, A. Bonito-Oliva, T.P. Sakmar, Update on Alzheimer’s Disease Therapy and Prevention Strategies, Annu. Rev. Med. 68 (2017) 413–430.
S.L. Rogers, R.S. Doody, R.C. Mohs, L.T. Friedhoff, Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group, Arch. Intern. Med. 158 (1998) 1021–1031.
H. Sugimoto, Donepezil hydrochloride: a treatment drug for Alzheimer’s disease, Chem. Rec. 1 (2001) 63–73.
H. Sugimoto, H. Ogura, Y. Arai, Y. Limura, Y. Yamanishi, Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor, Jpn. J. Pharmacol. 89 (2002) 7–20.
G.T. Grossberg, C. Sadowsky, J.T. Olin, Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer’s disease, Int. J. Clin. Pract. 64 (2010) 651–660.
K. Articus, M. Baier, F. Tracik, F. Kuhn, U.W. Preuss, A. Kurz, A 24-week, multicentre, open evaluation of the clinical effectiveness of the rivastigmine patch in patients with probable Alzheimer’s disease, Int. J. Clin. Pract. 65 (2011) 790–796.
R. Khoury, J. Rajamanickam, G.T. Grossberg, An update on the safety of current therapies for Alzheimer’s disease: focus on rivastigmine, Ther. Adv. Drug Saf. 9 (2018) 171–178.
D. Prvulovic, H. Hampel, J. Pantel, Galantamine for Alzheimer’s disease, Expert Opin. Drug Metab. Toxicol. 6 (2010) 345–354.
M.A. Raskind, Update on Alzheimer drugs (galantamine), Neurologist 9 (2003) 235–240.
S. Matsunaga, T. Kishi, I. Nomura, K. Sakuma, M. Okuya, T. Ikuta, N. Iwata, The efficacy and safety of memantine for the treatment of Alzheimer’s disease, Expert Opin. Drug Saf. 17 (2018) 1053–1061.
D. Galimberti, E. Scarpini, Old and new acetylcholinesterase inhibitors for Alzheimer’s disease, Expert Opin. Invest. Drugs 25 (2016) 1181–1187.
R.T. Bartus, R.L. Dean, B. Beer, A.S. Lippa, The cholinergic hypothesis of geriatric memory dysfunction, Science 217 (1982) 408–414.
P. Davies, A.J. Maloney, Selective loss of central cholinergic neurons in Alzheimer’s disease, Lancet 2 (1976) 1403.
D. Wu, L.B. Hersh, Choline acetyltransferase: celebrating its fiftieth year, J. Neurochem. 62 (1994) 1653–1663.
T.H. Ferreira-Vieira, I.M. Guimaraes, F.R. Silva, F.M. Ribeiro, Alzheimer’s disease: Targeting the Cholinergic System, Curr. Neuropharmacol. 14 (2016) 101–115.
P. Taylor, Z. Radic, The cholinesterases: from genes to proteins, Annu. Rev. Pharmacol. Toxicol. 34 (1994) 281–320.
P. Guyenet, P. Lefresne, J. Rossier, J.C. Beaujouan, J. Glowinski, Inhibition by hemicholinium-3 of (14C)acetylcholine synthesis and (3H)choline high-affinity uptake in rat striatal synaptosomes, Mol. Pharmacol. 9 (1973) 630–639.
A. Rampa, S. Montanari, L. Pruccoli, M. Bartolini, F. Falchi, A. Feoli, A. Cavalli, F. Belluti, S. Gobbi, A. Tarozzi, A. Bisi, Chalcone-based carbamates for Alzheimer’s disease treatment, Future Med. Chem. 9 (2017) 749–764.
54. G. Xiao, Y. Li, X. Qiang, R. Xu, Y. Zheng, Z. Cao, L. Luo, X. Yang, Z. Sang, F. Su, Y. Deng, Design, synthesis and biological evaluation of 4’-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease, Bioorg. Med. Chem. 25 (2017) 1030–1041.
H.R. Liu, X.J. Liu, H.Q. Fan, J.J. Tang, X.H. Gao, W.K. Liu, Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors, Bioorg. Med. Chem. 22 (2014) 6124–6133.
H.R. Liu, C. Zhou, H.Q. Fan, J.J. Tang, L.B. Liu, X.H. Gao, Q.A. Wang, W.K. Liu, Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer’s Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives, Chem. Biol. Drug Des. 86 (2015) 517–522.
X.H. Gao, C. Zhou, H.R. Liu, L.B. Liu, J.J. Tang, X.H. Xia, Tertiary amine derivatives of chlorochalcone as acetylcholinesterase (AChE) and buthylcholinesterase (BuChE) inhibitors: the influence of chlorine, alkyl amine side chain and alpha, beta-unsaturated ketone group, J. Enzyme Inhib. Med. Chem. 32 (2017) 146–152.
L. Huang, H. Miao, Y. Sun, F. Meng, X. Li, Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer’s disease, Eur. J. Med. Chem. 87 (2014) 429–439.
C.B. Mishra, S. Kumari, A. Manral, A. Prakash, V. Saini, A.M. Lynn, M. Tiwari, Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease, Eur. J. Med. Chem. 125 (2017) 736–750.
Sukumaran SD, Chee CF, Viswanathan G, et al. Synthesis, biological evaluation and molecular modelling of 2′-hydroxychalcones as acetylcholinesterase inhibitors. Molecules 2016; 21(7): 955.
Rampa A, Bartolini M, Pruccoli L, et al. Exploiting the chalcone scaffold to develop multifunctional agents for Alzheimer’s disease. Molecules 2018; 23(8): 1902.
Sagar SR, Singh DP, Das RD, Panchal NB, Sudarsanam V, Nivsarkar M, Vasu KK. Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer’s disease. Bioorganic chemistry. 2019 Aug 1;89:102992.
Kanhed AM, Patel DV, Patel NR, Sinha A, Thakor PS, Patel KB, Prajapati NK, Patel KV, Yadav MR. Indoloquinoxaline derivatives as promising multi-functional anti-Alzheimer agents. Journal of Biomolecular Structure and Dynamics. 2020 Oct 27:1-8.
Mahajan S, Slathia N, Nuthakki VK, Bharate SB, Kapoor KK. Malononitrile-activated synthesis and anti-cholinesterase activity of styrylquinoxalin-2 (1 H)-ones. RSC Advances. 2020;10(27):15966-75.