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DOI: 10.1055/a-2231-1311
In-silico, Synthesis, Characterization, and In-vitro Studies on Benzylidene-based 2-chloroquinolin Derivatives as Free Radical Scavengers in Parkinson’s Disease
Abstract
Parkinson’s disease is the loss of dopaminergic neurons in the substantial nigra part of the brain leading to neurodegeneration. Whereas, reactive oxygen species and mitochondrial impairment are considered to be the major pathophysiology of neurodegeneration. The benzylidene-based 2-chloroquinolin derivatives were synthesized and characterized by FT-IR, NMR, and MS spectrometry which were screened using various in-silico approaches. The designed compounds were further assessed using in-vitro cytotoxicity assay by the MTT method, DPPH assay, and Glutathione measurements in the SHSY5Y neuroblastoma cell lines. The compounds JD-7 and JD-4 were found to have a binding affinity of − 7.941 and − 7.633 kcal/mol with an MMGBSA score of − 64.614 and − 62.817 kcal/mol. The compound JD-7 showed the highest % Cell viability of 87.64% at a minimal dose of 125 µg/mL by the MTT method. The neurotoxicity effects were observed at increasing concentrations from 0 to 125, 250, and 500 µg/mL. Further, free radical scavenging activity for the JD-7 was found to be 36.55 at lowest 125 µg/mL concentrations. At 125 µg/mL, GSH % and GSSG % were found to be increasing in rotenone treatment, whereas JD-7 and JD-4 were found in the downregulation of glutathione level in the pre-treated rotenone SHSY5Y neuroblastoma cell lines. The benzylidene-based chloroquinolin derivatives were synthesized, and among the compounds JD-1 to JD-13, the compounds JD-7, and JD-4 were found to have having highest % cell viability, free radical scavenging molecules, and glutathione levels in the SHSY5Y neuroblastoma cell lines and could be used as free radical scavengers in Parkinson’s disease.
Key words
in-silico studies - reactive oxygen species - SHSY5Y neuroblastoma cell lines - in-vitro studies - neurodegeneration - Parkinson’s diseasePublication History
Received: 16 November 2023
Accepted: 11 December 2023
Article published online:
12 February 2024
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References
- 1 El-Shorbagi AN, Chaudhary S, Alshemali KA. et al. A comprehensive review on management of Parkinson’s disease, inclusive of drug discovery and pharmacological approaches. J Appl Pharm Sci 2020; 10: 130-150 DOI: 10.7324/JAPS.2020.1010015.
- 2 Subramanian G, Chand J, Jupudi S. et al. Synthesis and Biological Evaluation of the Selected Naphthalene Substituted Azetidinone Derivatives Targeting Parkinson’s Disease. Indian Journal of Pharmaceutical Education and Research 2023; 57: 552-558 DOI: 10.5530/ijper.57.2.68.
- 3 Cheong SL, Federico S, Spalluto G. et al. The current status of pharmacotherapy for the treatment of Parkinson’s disease: transition from single-target to multitarget therapy. Drug Discov Today 2019; 24: 1769-1783 DOI: 10.1016/j.drudis.2019.05.003.
- 4 Zhang Y, Xu X. Chinese Herbal Medicine in the Treatment of Depression in Parkinson’s Disease: From Molecules to Systems. Front Pharmacol 2022; 13: 879459 DOI: 10.3389/fphar.2022.879459.
- 5 Dorszewska J, Kowalska M, Prendecki M. et al. Oxidative stress factors in Parkinson’s disease. Neural Regen Res 2021; 16: 1383-1391 DOI: 10.4103/1673-5374.300980.
- 6 Sawa K, Uematsu T, Korenaga Y. et al. Krebs cycle intermediates protective against oxidative stress by modulating the level of reactive oxygen species in neuronal HT22 cells. Antioxidants 2017; 6 (21) DOI: 10.3390/antiox6010021.
- 7 Sawa K, Uematsu T, Korenaga Y. et al. Regulation of SIRT3 on mitochondrial functions and oxidative stress in Parkinson’s disease. Biomedicine and Pharmacotherapy 2020; 132: 110928 DOI: 10.1016/j.biopha.2020.110928.
- 8 Lagouge M, Argmann C, Gerhart-Hines Z. et al. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α. Cell 2006; 127: 1109-1122 DOI: 10.1016/j.cell.2006.11.013.
- 9 Zhang B, Zhai M, Li B. et al. Honokiol ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by reducing oxidative stress and apoptosis through activating the SIRT1-Nrf2 signaling pathway. Oxid Med Cell Longev 2018; 2018 DOI: 10.1155/2018/3159801.
- 10 Baeken MW, Schwarz M, Kern A. et al. The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites. Cell Death Discov 2021; 7: 286 DOI: 10.1038/s41420-021-00683-x.
- 11 Zang H, Yang W, Tian X. Simvastatin in the Treatment of Colorectal Cancer . A Review 2022; 2022: 3827933
- 12 Jia CY, Li JY, Hao GF. et al. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today 2020; 25: 248-258 DOI: 10.1016/j.drudis.2019.10.014.
- 13 Zhang J, Xiang H, Liu J. et al. Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target. Theranostics 2020; 10: 8315-8342 DOI: 10.7150/thno.45922.
- 14 Chen YL, Fu LL, Wen X. et al. Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis 2014; 5: 1-7 DOI: 10.1038/cddis.2014.14.
- 15 Lu J, Zhang H, Chen X. et al. A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. Free Radic Biol Med 2017; 112: 287-297 DOI: 10.1016/j.freeradbiomed.2017.07.012.
- 16 El Faydy M, Dahaieh N, Ounine K. et al. Synthesis, Identification, Antibacterial Activity, ADME/T and 1BNA-Docking Investigations of 8-Quinolinol Analogs Bearing a Benzimidazole Moiety. Arab J Sci Eng 2022; 47: 497-510 DOI: 10.1007/s13369-021-05749-7.
- 17 Szczepankiewicz BG, Dai H, Koppetsch KJ. et al. Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5. Journal of Organic Chemistry 2012; 77: 7319-7329 DOI: 10.1021/jo301067e.
- 18 Hasan MM, Khan Z, Chowdhury MS. et al. In silico molecular docking and ADME/T analysis of Quercetin compound with its evaluation of broad-spectrum therapeutic potential against particular diseases. Inform Med Unlocked 2022; 29: 100894 DOI: 10.1016/j.imu.2022.100894.
- 19 Ajiboye BO, Fagbola TM, Folorunso IM. et al. In silico identification of chemical compounds in Spondias mombin targeting aldose reductase and glycogen synthase kinase 3β to abate diabetes mellitus. Inform Med Unlocked 2023; 36: 101126 DOI: 10.1016/j.imu.2022.101126.
- 20 Ahmad F. Ganoderic Acid A targeting leucine-rich repeat kinase 2 involved in Parkinson’s disease–A computational study. Aging Medicine 2023; 6: 272-280 DOI: 10.1002/agm2.12235.
- 21 Ranade SD, Alegaon SG, Venkatasubramanian U. et al. Design, synthesis, molecular dynamics simulation, MM/GBSA studies and kinesin spindle protein inhibitory evaluation of some 4-aminoquinoline hybrids. Comput Biol Chem 2023; 105: 107881 DOI: 10.1016/j.compbiolchem.2023.107881.
- 22 Abdi B, Fekadu M, Zeleke D. et al. Synthesis and Evaluation of the Antibacterial and Antioxidant Activities of Some Novel Chloroquinoline Analogs. J Chem 2021; 2021 DOI: 10.1155/2021/2408006.
- 23 Moghaddam FM, Moafi A, Ziadkhani A. et al. A Facile and Efficient Route for the Synthesis of Thiopyranoquinolines-Fused Indole Moiety Using 2-Chloroquinoline-3-carbaldehydes. Chemistry Select 2019; 4: 11683-11686 DOI: 10.1002/slct.201902476.
- 24 Ghandi M, Efteghar I, Abbasi A. One-pot synthesis of quinoline-fused [1,4]thiazepines via the tandem Ugi/post-Ugi reactions. J Iran Chem Soc 2019; 16: 325-332 DOI: 10.1007/s13738-018-1511-z.
- 25 Hamama WS, Ibrahim ME, Gooda AA. et al. Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs. RSC Adv 2018; 8: 8484-8515
- 26 Silverberg LJ, Coyle DJ, Cannon KC. et al. Azeotropic Preparation of a C-Phenyl N-Aryl Imine: An Introductory Undergraduate Organic Chemistry Laboratory Experiment. J Chem Educ 2016; 93: 941-944 DOI: 10.1021/acs.jchemed.6b00056.
- 27 Bergemann C, Rebl H, Otto A. et al. Pyruvate as a cell-protective agent during cold atmospheric plasma treatment in vitro: Impact on basic research for selective killing of tumor cells. Plasma Process Polym 2019; 16 DOI: 10.1002/ppap.201900088.
- 28 Wei PC, Lee-Chen GJ, Chen CM. et al. Neuroprotection of Indole-Derivative Compound NC001-8 by the Regulation of the NRF2 Pathway in Parkinson’s Disease Cell Models. Oxid Med Cell Longev 2019; 2019 DOI: 10.1155/2019/5074367.
- 29 Singh CK, Chhabra G, Ndiaye MA. et al. The Role of Sirtuins in Antioxidant and Redox Signaling. Antioxid Redox Signal 2018; 28: 643-661
- 30 Abu Shelbayeh O, Arroum T, Morris S. et al. PGC-1α Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response. Antioxidants 2023; 12
- 31 Di Meo S, Venditti P. Evolution of the Knowledge of Free Radicals and Other Oxidants. Oxid Med Cell Longev. 2020 2020.
- 32 Agahi F, Alvarez-Ortega N, Font G. et al. Oxidative stress, glutathione, and gene expression as key indicators in SH-SY5Y cells exposed to zearalenone metabolites and beauvericin. Toxicol Lett 2020; 334: 44-52 DOI: 10.1016/j.toxlet.2020.09.011.
- 33 Wiatrak B, Jawień P, Matuszewska A. et al. Effect of amyloid-β on the redox system activity in SH-SY5Y cells preincubated with lipopolysaccharide or co-cultured with microglia cells. Biomed Pharmacother 2022; 149: 112880 DOI: 10.1016/j.biopha.2022.112880.
- 34 Li Y, Ye Z, Lai W. et al. Activation of sirtuin 3 by silybin attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury. Front Pharmacol 2017; 8 DOI: 10.3389/fphar.2017.00178.
- 35 Prabhakaran P, Nadig A, Tuladhar S. et al. Design and Development of Novel Glitazones for Activation of PGC-1α Signaling Via PPAR-γ Agonism: A Promising Therapeutic Approach against Parkinson’s Disease. ACS Omega 2023; 8: 6825-6837 DOI: 10.1021/acsomega.2c07521.
- 36 Kolodkin N, Sharma A, Colangelo RP. et al. ROS networks: designs, aging, Parkinson’s disease and precision therapies. NPJ Syst Biol Appl 2020; 6: 35 DOI: 10.1038/s41540-020-00150-w.
- 37 Chang KH, Chen CM. The role of oxidative stress in Parkinson’s disease. Antioxidants 2020; 9: 1-32