{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:31:20Z","timestamp":1790353880784,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer\u2019s disease (AD) is a multifaceted neurodegenerative condition. The pathogenesis of AD is highly intricate and the disease is apparent in the aged population\u2009~\u200950\u201370\u00a0years old. Even after\u2009&gt;\u2009100\u00a0years of research, the root origin of AD and its pathogenesis is unclear, complex and multifaceted. Herein, we have designed and synthesized 9 novel molecules with three different heterocyclic scaffolds namely pyrrolidone-2-one, quinoline &amp; indoline-2-one to imitate and explore the novel chemical space around donepezil. The synthesized molecules were evaluated for their potential as anti-Alzheimer\u2019s agents through <jats:italic>in-vitro<\/jats:italic> and <jats:italic>in-vivo<\/jats:italic> studies in appropriate animal models. To further understand their interaction with acetylcholinesterase enzyme (AChE), extra-precision docking, and molecular dynamics simulation studies were carried out. As the number of compounds was limited to thoroughly explore the structure\u2013activity relationship, atom-based 3D-quantitative structure\u2013activity relationships (QSAR) studies were carried out to get more insights. All the designed compounds were found to inhibit AChE with IC<jats:sub>50<\/jats:sub> in the micromolar range. From pyrrolidone-2-one series, 6-chloro-N-(1-(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)pyridine-3-sulfonamide (<jats:bold>9<\/jats:bold>), 2-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline (<jats:bold>18<\/jats:bold>) from quinoline series and N-(1-benzylpiperidin-4-yl)-2-(2-oxoindolin-3-yl)acetamide (<jats:bold>23<\/jats:bold>) from indolin-2-one series inhibited AChE with an IC<jats:sub>50<\/jats:sub> value of 0.01\u00a0\u00b5M. Based on other biochemical studies like lipid peroxidation, reduced glutathione, superoxide dismutase, catalase, nitrite, and behavioural studies (Morris water maze), compound <jats:bold>9<\/jats:bold> was found to be a potent AChE inhibitor which can be further explored as a lead molecule to design more potent and effective anti-Alzheimer\u2019s agents.<\/jats:p>","DOI":"10.1038\/s41598-024-51713-4","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T08:02:26Z","timestamp":1705651346000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Investigation, scaffold hopping of novel donepezil-based compounds as anti-Alzhiemer\u2019s agents: synthesis, in-silico and pharmacological evaluations"],"prefix":"10.1038","volume":"14","author":[{"given":"Mohan","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Pant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preeti","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chakrawarti","family":"Prasun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya S.","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarvesh","family":"Paliwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumitra","family":"Nain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"51713_CR1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","volume":"14","author":"MA DeTure","year":"2019","unstructured":"DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer\u2019s disease. Mol. Neurodegener. 14, 32 (2019).","journal-title":"Mol. Neurodegener."},{"key":"51713_CR2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","volume":"396","author":"G Livingston","year":"2020","unstructured":"Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413\u2013446 (2020).","journal-title":"Lancet"},{"key":"51713_CR3","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1021\/acschemneuro.0c00403","volume":"11","author":"M Gupta","year":"2020","unstructured":"Gupta, M., Ojha, M., Yadav, D., Pant, S. & Yadav, R. Novel benzylated (pyrrolidin-2-one)\/(imidazolidin-2-one) derivatives as potential anti-alzheimer\u2019s agents: Synthesis and pharmacological investigations. ACS Chem. Neurosci. 11, 2849\u20132860 (2020).","journal-title":"ACS Chem. Neurosci."},{"key":"51713_CR4","doi-asserted-by":"publisher","first-page":"962","DOI":"10.2174\/1389557522666220922105934","volume":"23","author":"M Gupta","year":"2023","unstructured":"Gupta, M., Kumar, A., Ojha, M., Khan, S. K. & Nain, S. A recent appraisal of small-organic molecules as anti-Alzheimer\u2019s agents. Mini-Rev. Med. Chem. 23, 962\u2013976 (2023).","journal-title":"Mini-Rev. Med. Chem."},{"key":"51713_CR5","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.ejmech.2016.07.052","volume":"123","author":"Z-M Wang","year":"2016","unstructured":"Wang, Z.-M. et al. Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer\u2019s disease. Eur. J. Med. Chem. 123, 282\u2013297 (2016).","journal-title":"Eur. J. Med. Chem."},{"key":"51713_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103328","volume":"93","author":"R Cai","year":"2019","unstructured":"Cai, R., Wang, L.-N., Fan, J.-J., Geng, S.-Q. & Liu, Y.-M. New 4-N-phenylaminoquinoline derivatives as antioxidant, metal chelating and cholinesterase inhibitors for Alzheimer\u2019s disease. Bioorg. Chem. 93, 103328 (2019).","journal-title":"Bioorg. Chem."},{"key":"51713_CR7","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0165-0270(84)90007-4","volume":"11","author":"R Morris","year":"1984","unstructured":"Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47\u201360 (1984).","journal-title":"J. Neurosci. Methods"},{"key":"51713_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4061\/2009\/972178","volume":"2009","author":"A Kumar","year":"2009","unstructured":"Kumar, A., Dogra, S. & Prakash, A. Neuroprotective effects of centella asiatica against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress. Int. J. Alzheimers. Dis. 2009, 1\u20138 (2009).","journal-title":"Int. J. Alzheimers. Dis."},{"key":"51713_CR9","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","volume":"7","author":"GL Ellman","year":"1961","unstructured":"Ellman, G. L., Courtney, K. D., Andres, V. & Featherstone, R. M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7, 88\u201395 (1961).","journal-title":"Biochem. Pharmacol."},{"key":"51713_CR10","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1042\/bj0990667","volume":"99","author":"E Wills","year":"1966","unstructured":"Wills, E. Mechanisms of lipid peroxide formation in animal tissues. Biochem. J. 99, 667\u2013676 (1966).","journal-title":"Biochem. J."},{"key":"51713_CR11","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/0003-9861(59)90090-6","volume":"82","author":"GL Ellman","year":"1959","unstructured":"Ellman, G. L. Tissue sulfhydryl groups. Arch. Biochem. Biophys. 82, 70\u201377 (1959).","journal-title":"Arch. Biochem. Biophys."},{"key":"51713_CR12","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0003-9861(78)90479-4","volume":"186","author":"Y Kono","year":"1978","unstructured":"Kono, Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch. Biochem. Biophys. 186, 189\u2013195 (1978).","journal-title":"Arch. Biochem. Biophys."},{"key":"51713_CR13","doi-asserted-by":"publisher","unstructured":"L\u00fcck, H. Catalase. In Methods of Enzymatic Analysis 885\u2013894 (Elsevier, 1965). https:\/\/doi.org\/10.1016\/B978-0-12-395630-9.50158-4","DOI":"10.1016\/B978-0-12-395630-9.50158-4"},{"key":"51713_CR14","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","volume":"126","author":"LC Green","year":"1982","unstructured":"Green, L. C. et al. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal. Biochem. 126, 131\u2013138 (1982).","journal-title":"Anal. Biochem."},{"key":"51713_CR15","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"G Madhavi Sastry","year":"2013","unstructured":"Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Mol. Des. 27, 221\u2013234 (2013).","journal-title":"J. Comput. Mol. Des."},{"key":"51713_CR16","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","volume":"15","author":"K Roos","year":"2019","unstructured":"Roos, K. et al. OPLS3e: Extending force field coverage for drug-like small molecules. J. Chem. Theory Comput. 15, 1863\u20131874 (2019).","journal-title":"J. Chem. Theory Comput."},{"key":"51713_CR17","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"G Madhavi Sastry","year":"2013","unstructured":"Madhavi Sastry, G., Adzhigirey, M., Day, T., Annabhimoju, R. & Sherman, W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided. Mol. Des. 27, 221\u2013234 (2013).","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"51713_CR18","doi-asserted-by":"publisher","DOI":"10.1007\/s11696-023-02971-5","author":"A Kumar","year":"2023","unstructured":"Kumar, A., Prasun, C., Rathi, E., Nair, M. S. & Kini, S. G. Identification of potential DNA gyrase inhibitors: virtual screening, extra-precision docking and molecular dynamics simulation study. Chem. Pap. https:\/\/doi.org\/10.1007\/s11696-023-02971-5 (2023).","journal-title":"Chem. Pap."},{"key":"51713_CR19","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1021\/jm0306430","volume":"47","author":"RA Friesner","year":"2004","unstructured":"Friesner, R. A. et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739\u20131749 (2004).","journal-title":"J. Med. Chem."},{"key":"51713_CR20","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.2174\/1389557521666210401091147","volume":"21","author":"A Kumar","year":"2021","unstructured":"Kumar, A., Kini, S. G. & Rathi, E. A recent appraisal of artificial intelligence and in silico ADMET prediction in the early stages of drug discovery. Mini-Rev. Med. Chem. 21, 2786\u20132798 (2021).","journal-title":"Mini-Rev. Med. Chem."},{"key":"51713_CR21","unstructured":"Schr\u00f6dinger Release 2023\u20133: QikProp, Schr\u00f6dinger, LLC, New York, NY, 2023. https:\/\/www.schrodinger.com\/products\/qikprop."},{"key":"51713_CR22","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","volume":"91","author":"HJC Berendsen","year":"1995","unstructured":"Berendsen, H. J. C., van der Spoel, D. & van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun. 91, 43\u201356 (1995).","journal-title":"Comput. Phys. Commun."},{"key":"51713_CR23","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1007\/s10822-006-9087-6","volume":"20","author":"SL Dixon","year":"2006","unstructured":"Dixon, S. L. et al. PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J. Comput. Aided. Mol. Des. 20, 647\u2013671 (2006).","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"51713_CR24","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1080\/14756366.2016.1201814","volume":"31","author":"F Li","year":"2016","unstructured":"Li, F. et al. Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase\/monoamine oxidase inhibitors for the potential application against Alzheimer\u2019s disease. J. Enzyme Inhib. Med. Chem. 31, 41\u201353 (2016).","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"51713_CR25","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1080\/14756366.2016.1256883","volume":"32","author":"J-S Lan","year":"2017","unstructured":"Lan, J.-S. et al. Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer\u2019s disease. J. Enzyme Inhib. Med. Chem. 32, 776\u2013788 (2017).","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"51713_CR26","doi-asserted-by":"publisher","first-page":"6282","DOI":"10.1080\/07391102.2022.2106515","volume":"41","author":"M Gupta","year":"2023","unstructured":"Gupta, M. et al. Design, synthesis, extra-precision docking, and molecular dynamics simulation studies of pyrrolidin-2-one derivatives as potential acetylcholinesterase inhibitors. J. Biomol. Struct. Dyn. 41, 6282\u20136294 (2023).","journal-title":"J. Biomol. Struct. Dyn."},{"key":"51713_CR27","doi-asserted-by":"publisher","first-page":"9403","DOI":"10.3390\/molecules19079403","volume":"19","author":"M Pervin","year":"2014","unstructured":"Pervin, M. et al. Antioxidant activity and acetylcholinesterase inhibition of grape skin anthocyanin (GSA). Molecules 19, 9403\u20139418 (2014).","journal-title":"Molecules"},{"key":"51713_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103524","volume":"95","author":"CB Mishra","year":"2020","unstructured":"Mishra, C. B. et al. Development of novel carbazole derivatives with effective multifunctional action against Alzheimer\u2019s diseases: Design, synthesis, in silico, in vitro and in vivo investigation. Bioorg. Chem. 95, 103524 (2020).","journal-title":"Bioorg. Chem."},{"key":"51713_CR29","doi-asserted-by":"publisher","first-page":"17602","DOI":"10.1039\/D0RA00663G","volume":"10","author":"CB Mishra","year":"2020","unstructured":"Mishra, C. B. et al. Development of novel N -(6-methanesulfonyl-benzothiazol-2-yl)-3-(4-substituted-piperazin-1-yl)-propionamides with cholinesterase inhibition, anti-\u03b2-amyloid aggregation, neuroprotection and cognition enhancing properties for the therapy of Alzheimer\u2019s dise. RSC Adv. 10, 17602\u201317619 (2020).","journal-title":"RSC Adv."},{"key":"51713_CR30","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/j.ejmech.2016.09.057","volume":"125","author":"CB Mishra","year":"2017","unstructured":"Mishra, C. B. et al. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer\u2019s disease. Eur. J. Med. Chem. 125, 736\u2013750 (2017).","journal-title":"Eur. J. Med. Chem."},{"key":"51713_CR31","doi-asserted-by":"publisher","first-page":"15236","DOI":"10.1038\/s41598-022-18224-6","volume":"12","author":"H Pourtaher","year":"2022","unstructured":"Pourtaher, H., Hasaninejad, A. & Iraji, A. Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer\u2019s disease. Sci. Rep. 12, 15236 (2022).","journal-title":"Sci. Rep."},{"key":"51713_CR32","doi-asserted-by":"publisher","first-page":"15546","DOI":"10.1038\/s41598-023-42239-2","volume":"13","author":"AM Soliman","year":"2023","unstructured":"Soliman, A. M. et al. Novel iodoquinazolinones bearing sulfonamide moiety as potential antioxidants and neuroprotectors. Sci. Rep. 13, 15546 (2023).","journal-title":"Sci. Rep."},{"key":"51713_CR33","doi-asserted-by":"publisher","first-page":"811","DOI":"10.3390\/ijms23020811","volume":"23","author":"ME Bragina","year":"2022","unstructured":"Bragina, M. E., Daina, A., Perez, M. A. S., Michielin, O. & Zoete, V. The SwissSimilarity 2021 Web Tool: Novel chemical libraries and additional methods for an enhanced ligand-based virtual screening experience. Int. J. Mol. Sci. 23, 811 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"51713_CR34","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ejphar.2009.04.058","volume":"615","author":"P Kumar","year":"2009","unstructured":"Kumar, P. & Kumar, A. Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington\u2019s disease like symptoms: Possible behavioural, biochemical and cellular alterations. Eur. J. Pharmacol. 615, 91\u2013101 (2009).","journal-title":"Eur. J. Pharmacol."},{"key":"51713_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/974013","volume":"2012","author":"P Goverdhan","year":"2012","unstructured":"Goverdhan, P., Sravanthi, A. & Mamatha, T. neuroprotective effects of meloxicam and selegiline in scopolamine-induced cognitive impairment and oxidative stress. Int. J. Alzheimers. Dis. 2012, 1\u20138 (2012).","journal-title":"Int. J. Alzheimers. Dis."},{"key":"51713_CR36","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.ejphar.2007.12.009","volume":"581","author":"G Saxena","year":"2008","unstructured":"Saxena, G., Singh, S. P., Agrawal, R. & Nath, C. Effect of donepezil and tacrine on oxidative stress in intracerebral streptozotocin-induced model of dementia in mice. Eur. J. Pharmacol. 581, 283\u2013289 (2008).","journal-title":"Eur. J. Pharmacol."},{"key":"51713_CR37","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.bbr.2012.03.015","volume":"232","author":"S Tota","year":"2012","unstructured":"Tota, S., Nath, C., Najmi, A. K., Shukla, R. & Hanif, K. Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: Role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism. Behav. Brain Res. 232, 66\u201376 (2012).","journal-title":"Behav. Brain Res."},{"key":"51713_CR38","first-page":"45","volume":"1","author":"R Kaur","year":"2015","unstructured":"Kaur, R., Parveen, S., Mehan, S., Khanna, D. & Kalra, S. Neuroprotective effect of ellagic acid against chronically scopolamine induced Alzheimer\u2019s type memory and cognitive dysfunctions: Possible behavioural and biochemical evidences. Int. J. Prev. Med. Res. 1, 45\u201364 (2015).","journal-title":"Int. J. Prev. Med. Res."},{"key":"51713_CR39","first-page":"7532","volume":"11","author":"D Jianyang","year":"2019","unstructured":"Jianyang, D. et al. Metal-, photocatalyst-, and light-free minisci C-H alkylation of N-heteroarenes with oxalates. J. Org. Chem. 11, 7532\u20137540 (2019).","journal-title":"J. Org. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-51713-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-51713-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-51713-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T12:30:02Z","timestamp":1705926602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-51713-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,19]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["51713"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-51713-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,19]]},"assertion":[{"value":"25 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1687"}}