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Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease

Year 2024, Volume: 28 Issue: 5, 1344 - 1356, 28.06.2025

Burcu Kılıç

Abstract

Alzheimer’s Disease (AD) is one of the most devastating chronic health problems of the last few decades. Unfortunately, current treatment and care options for AD are insufficient, making it a prominent topic for drug discovery studies. Currently, AD drug development studies have focused on the strategy of multitarget directed ligands (MTDLs). Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, we designed and synthesized novel eight N’-(4-oxo-4H-chromen-3-yl)methylene propanehydrazide derivatives. We then evaluated the inhibition potency of all final compounds for cholinesterase enzymes. Among them, (6f) (IC50 AChE=16.91 µM) was found to be the most potent acetylcholinesterase inhibitor. Additionally, (6d) (IC50’s AChE=26.91 µM and BChE=47.94 µM) exhibited dual cholinesterase inhibitor activity. Moreover, we investigated all title compounds for their antioxidant (DPPH, ORAC) and metal chelator activities. According to the ORAC-FL results, all the compounds exhibited good antioxidant activity ranging from 4.082 to 16.715 Trolox equivalents. We also observed chelator effects of all compounds for Cu(II), Fe(II), and Zn(II) ions at varying rates. Furthermore, we assessed the in-silico physicochemical parameters of the compounds to evaluate their drug-likeness or druggability.

Keywords

Chromene cholinesterase inhibition antioxidant metal-chelator alzheimer’s disease

References

  • [1] World Alzheimer Report 2019: Attitudes to Dementia. Alzheimer’s Disease International (ADI) 2019. https://www.alzint.org/u/WorldAlzheimerReport2019.pdf (accessed on 23 October 2023).
  • [2] 2023 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2023; 19(4): 1598-1695. https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf (accessed on 23 October 2023).
  • [3] Kumar A, Singh A, Ekavali. A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol Rep. 2015; 67(2): 195-203. https://doi.org/10.1016/j.pharep.2014.09.004
  • [4] DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019; 14(1): 32. https://doi.org/10.1186/s13024-019-0333-5
  • [5] Blaikie L, Kay G, Kong Thoo Lin P. Current and emerging therapeutic targets of alzheimer's disease for the design of multi-target directed ligands. MedChemComm. 2019; 10(12): 2052-2072. http://dx.doi.org/10.1039/C9MD00337A
  • [6] Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008; 51(3): 347-372. https://doi.org/10.1021/jm7009364
  • [7] Li Q, Xing S, Chen Y, Liao Q, Xiong B, He S, Lu W, Liu Y, Yang H, Li Q, Feng F, Liu W, Chen Y, Sun H. Discovery and biological evaluation of a novel highly potent selective butyrylcholinsterase inhibitor. J Med Chem. 2020; 63(17): 10030-10044. https://doi.org/10.1021/acs.jmedchem.0c01129
  • [8] Chen Y, Lin H, Yang H, Tan R, Bian Y, Fu T, Wei Li, Wu L, Pei Y , Sun H. Discovery of new acetylcholinesterase and butyrylcholinesterase inhibitors through structure-based virtual screening. RSC Adv. 2017; 7(6): 3429-3438. https://doi.org/10.1039/c6ra25887e
  • [9] Jing L, Wu G, Kang D, Zhou Z, Song Y, Liu X, Zhan P. Contemporary medicinal-chemistry strategies for the discovery of selective butyrylcholinesterase inhibitors. Drug Discov Today. 2019; 24(2): 629-635. https://doi.org/10.1016/j.drudis.2018.11.012
  • [10] Panek D, Pasieka A, Latacz G, Zaręba P, Szczęch M, Godyń J, Chantegreil F, Nachon F, Brazzolotto X, Wiercioch AS, Walczak M, Smolik M, Sałat K, Höfner G, Wanner K, Więckowska A, Malawska B. Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies. Eur J Med Chem. 2023; 249: 115135. https://doi.org/10.1016/j.ejmech.2023.115135
  • [11] Wichur T, Więckowska A, Więckowski K, Godyń J, Jończyk J, Valdivieso ÁdR, Panek D, Pasieka A, Sabaté R, Knez D, Gobec S, Malawska B. 1-Benzylpyrrolidine-3-amine-based BuChE inhibitors with anti-aggregating, antioxidant and metal-chelating properties as multifunctional agents against Alzheimer’s disease. Eur J Med Chem. 2020; 187: 111916. https://doi.org/10.1016/j.ejmech.2019.111916
  • [12] Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev. 2013; 2013: 316523. https://doi.org/10.1155/2013/316523
  • [13] Singh A, Kukreti R, Saso L, Kukreti S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules. 2019; 24(8):1583. https://doi.org/10.3390/molecules24081583
  • [14] Kenche VB, Barnham KJ. Alzheimer's disease & metals: therapeutic opportunities. Br J Pharmacol. 2011; 163(2): 211-219. https://doi.org/10.1111/j.1476-5381.2011.01221.x
  • [15] Mohsin NuA, Irfan M, Hassan Su, Saleem U. Current strategies in development of new chromone derivatives with diversified pharmacological activities: A review. Pharm Chem J. 2020; 54(3): 241-257. https://doi.org/10.1007/s11094-020-02187-x
  • [16] Hussain G, Zhang L, Rasul A, Anwar H, Sohail MU, Razzaq A, Aziz N, Shabbir A, Ali M, Sun T. Role of plant-derived flavonoids and their mechanism in attenuation of alzheimer's and Parkinson's Diseases: An update of recent data. Molecules. 2018; 23(4): 814. https://doi.org/10.3390/molecules23040814
  • [17] Costa M, Dias TA, Brito A, Proença F. Biological importance of structurally diversified chromenes. Eur J Med Chem. 2016; 123: 487-507. https://doi.org/10.1016/j.ejmech.2016.07.057
  • [18] Jiang N, Huang Q, Liu J, Liang N, Li Q, Li Q, Xie S. Design, synthesis and biological evaluation of new coumarin-dithiocarbamate hybrids as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2018; 146: 287-298. https://doi.org/10.1016/j.ejmech.2018.01.055
  • [19] Jalili-Baleh L, Nadri H, Forootanfar H, Samzadeh-Kermani A, Küçükkılınç TT, Ayazgok B, Rahimifard M, Baeeri M, Doostmohammadi M, Firoozpour L, Nasir S, Bukhari A, MR Ganjali, Emami S, Khoobi M, Foroumadi A. Novel 3-phenylcoumarin–lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease. Bioorg Chem. 2018; 79: 223-234. https://doi.org/10.1016/j.bioorg.2018.04.030
  • [20] Sun Q, Peng D-Y, Yang S-G, Zhu X-L, Yang W-C, Yang G-F. Syntheses of coumarin–tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase. Bioorg Med Chem. 2014; 22(17): 4784-4791. https://doi.org/10.1016/j.bmc.2014.06.057
  • [21] Wang D, Hu M, Li X, Zhang D, Chen C, Fu J, Shao S, Shi G, Zhou Y, Wu S, Zhang T . Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2019; 168: 207-220. https://doi.org/10.1016/j.ejmech.2019.02.053
  • [22] Estrada-Valencia M, Herrera-Arozamena C, Pérez C, Viña D, Morales-García JA, Pérez-Castillo A, Viña D, Garcia J, Castillo AP, Ramos E, Romeo A, Laurini E, Pricl S. New flavonoid – N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer´s disease endowed with neurogenic properties. J Enzyme Inhib Med Chem. 2019; 34(1): 712-727. https://doi.org/10.1080/14756366.2019.1581184
  • [23] Sharma K. Chromone scaffolds in the treatment of Alzheimer's and Parkinson's Disease: An overview. ChemistrySelect. 2022; 7(18): e202200540. https://doi.org/10.1002/slct.202200540
  • [24] Kilic B, Bardakkaya M, Ilıkcı Sagkan R, Aksakal F, Shakila S, Dogruer DS. New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation. Bioorg Chem. 2023; 131: 106322. https://doi.org/10.1016/j.bioorg.2022.106322
  • [25] Erdogan M, Kilic B, Sagkan RI, Aksakal F, Ercetin T, Gulcan HO, Dogruer DS. Design, synthesis and biological evaluation of new benzoxazolone/benzothiazolone derivatives as multi-target agents against Alzheimer's disease. Eur J Med Chem. 2021; 212: 113124. https://doi.org/10.1016/j.ejmech.2020.113124
  • [26] Kilic B, Erdogan M, Gulcan HO, Aksakarl F, Oruklu N, Bagriacik EU, Dogruer DS. Design, synthesis and investigation of new diphenyl substituted pyridazinone derivatives as both cholinesterase and a beta-aggregation inhibitors. Med Chem. 2019; 15(1): 59-76. https://dx.doi.org/10.2174/1573406414666180524073241
  • [27] Kilic B, Gulcan HO, Aksakal F, Ercetin T, Oruklu N, Umit Bagriacik E, Dogruer DS. Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase. Bioorg Chem. 2018; 79: 235-249. https://doi.org/10.1016/j.bioorg.2018.05.006
  • [28] Kilic B, Gulcan HO, Yalcın M, Aksakal F, Dimoglo A, Sahin MF. Synthesis of some new 1 (2H)-Phthalazinone derivatives and evaluation of their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Lett Drug Des Discov. 2017; 14(2): 159-166. https://doi.org/10.1007/s00044-014-1205-8
  • [29] Yamali C, Gulcan HO, Kahya B, Cobanoglu S, Sukuroglu MK, Dogruer DS. Synthesis of some 3(2H)-pyridazinone and 1(2H)-phthalazinone derivatives incorporating aminothiazole moiety and investigation of their antioxidant, acetylcholinesterase, and butyrylcholinesterase inhibitory activities. Med Chem Res. 2015; 24(3): 1210-1217. https://doi.org/10.1007/s00044-014-1205-8
  • [30] Bardakkaya M, Kilic B, Sagkan RI, Aksakal F, Shakila S, Dogruer DS. Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents. Arch Pharm. 2023; 356(8): 2300054. https://doi.org/10.1002/ardp.202300054
  • [31] Ostrowska K. Coumarin-piperazine derivatives as biologically active compounds. Saudi Pharm J. 2020; 28(2): 220-232. https://doi.org/10.1016/j.jsps.2019.11.025
  • [32] Bajda M, Wieckowska A, Hebda M, Guzior N, Sotriffer CA, Malawska B. Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci. 2013; 14(3): 5608-5632. https://doi.org/10.3390/ijms14035608
  • [33] Abouel-Enein SA, Emam SM, Abdel-Satar EM. Bivalent metal chelates with pentadentate azo-schiff base derived from nicotinic hydrazide: preparation, structural elucidation, and pharmacological activity. Chem Biodivers. 2023; 20(6): e202201223. https://doi.org/10.1002/cbdv.202201223
  • [34] Cao L, Zhang L, Cui P. Synthesis of 3-(3-Alkyl-5-thioxo-1H-4,5-dihydro-1,2,4-triazol-4-yl)aminocarbonylchromones. Chem Heterocycl Compd (NY). 2004; 40(5): 635-640. https://doi.org/10.1023/B:COHC.0000037320.27881.27
  • [35] Munir R, Javid N, Zia-ur-Rehman M, Zaheer M, Huma R, Roohi A, Athar Mm. Synthesis of novel N-acylhydrazones and their C-N/N-N bond conformational characterization by NMR spectroscopy. Molecules. 2021; 26(16): 4908. https://doi.org/10.3390/molecules26164908
  • [36] Palla G, Predieri G, Domiano P, Vignali C, Turner W. Conformational behaviour and E/Z isomerization of N-acyl and N-aroylhydrazones. Tetrahedron. 1986; 42(13): 3649-3654. https://doi.org/10.1016/S0040-4020(01)87332-4
  • [37] Bortolami M, Pandolfi F, De Vita D, Carafa C, Messore A, Di Santo R, Feroci M, Costi R, Chiarotto I, Bagetta D, Alcaro S, Colone M, Stringaro A, Scipione L. New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation. Eur J Med Chem. 2020; 198: 112350. https://doi.org/10.1016/j.ejmech.2020.112350
  • [38] Liu Y, Di Y, Liu M, Qiao C, Gao X, Zhou C. Synthesis, thermodynamic properties and Hirshfeld surface analysis of 2-[(4-methyl-benzoyl)-hydrazone]-propionic acid. J Mol Struct. 2022; 1260: 132792. https://doi.org/10.1016/j.molstruc.2022.132792
  • [39] Selvam P, Sathiyakumar S, Srinivasan K, Premkumar T. A Copper(II) complex of a new hydrazone: A solid-state single source precursor for the preparation of both Cu and CuO nanoparticles. J Mol Struct. 2019; 1177: 469-475. https://doi.org/10.1016/j.molstruc.2018.09.082
  • [40] Purandara H, Raghavendra S, Foro S, Patil P, Gowda BT, Dharmaprakash SM, Vishwanatha P. Synthesis, spectroscopic characterization, crystal structure, Hirshfeld surface analysis and third-order nonlinear optical properties of 2-(4-chlorophenoxy)-N'-[(1E)-1-(4-methylphenyl) ethylidene] acetohydrazide. J Mol Struct. 2019; 1185: 205-211. https://doi.org/10.1016/j.molstruc.2019.02.079
  • [41] Schrödinger Release 2021-3: QikProp, Schrödinger, LLC, New York, NY, 2021.
There are 41 citations in total.

Details

Primary Language English
Subjects Pharmaceutical Chemistry
Journal Section Articles
Authors

Burcu Kılıç 0000-0001-8737-829X

Publication Date June 28, 2025
Published in Issue Year 2024 Volume: 28 Issue: 5

Cite

APA Kılıç, B. (2025). Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease. Journal of Research in Pharmacy, 28(5), 1344-1356.
AMA Kılıç B. Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease. J. Res. Pharm. July 2025;28(5):1344-1356.
Chicago Kılıç, Burcu. “Design, Synthesis, and Biological Evaluation of Novel N’-(4-Oxo-4H-Chromen-3-Yl) Methylene Propanehydrazides for Alzheimer’s Disease”. Journal of Research in Pharmacy 28, no. 5 (July 2025): 1344-56.
EndNote Kılıç B (July 1, 2025) Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease. Journal of Research in Pharmacy 28 5 1344–1356.
IEEE B. Kılıç, “Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease”, J. Res. Pharm., vol. 28, no. 5, pp. 1344–1356, 2025.
ISNAD Kılıç, Burcu. “Design, Synthesis, and Biological Evaluation of Novel N’-(4-Oxo-4H-Chromen-3-Yl) Methylene Propanehydrazides for Alzheimer’s Disease”. Journal of Research in Pharmacy 28/5 (July 2025), 1344-1356.
JAMA Kılıç B. Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease. J. Res. Pharm. 2025;28:1344–1356.
MLA Kılıç, Burcu. “Design, Synthesis, and Biological Evaluation of Novel N’-(4-Oxo-4H-Chromen-3-Yl) Methylene Propanehydrazides for Alzheimer’s Disease”. Journal of Research in Pharmacy, vol. 28, no. 5, 2025, pp. 1344-56.
Vancouver Kılıç B. Design, synthesis, and biological evaluation of novel N’-(4-oxo-4H-chromen-3-yl) methylene propanehydrazides for Alzheimer’s disease. J. Res. Pharm. 2025;28(5):1344-56.