{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:11:01Z","timestamp":1767705061230,"version":"build-2065373602"},"reference-count":88,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a serious health concern, affecting millions of people globally, which leads to cognitive impairment, dementia, and inevitable death. There is still no medically accepted treatment for AD. Developing therapeutic treatments for AD is an overwhelming challenge in the medicinal field, as the exact mechanics underlying its devastating symptoms is still not completely understood. Rather than the unknown mechanism of the disease, one of the limiting factors in developing new drugs for AD is the blood\u2013brain barrier (BBB). A combination of nanotechnology with fluorinated molecules is proposed as a promising therapeutic treatment to meet the desired pharmacokinetic\/physiochemical properties for crossing the BBB passage. This paper reviews the research conducted on fluorine-containing compounds and fluorinated nanoparticles (NPs) that have been designed and tested for the inhibition of amyloid-beta (A\u03b2) peptide aggregation. Additionally, this study summarizes fluorinated molecules and NPs as promising agents and further future work is encouraged to be effective for the treatment of AD.<\/jats:p>","DOI":"10.3390\/ijms21082989","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"2989","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Fluorinated Molecules and Nanotechnology: Future \u2018Avengers\u2019 against the Alzheimer\u2019s Disease?"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-0117","authenticated-orcid":false,"given":"Meghna","family":"Dabur","sequence":"first","affiliation":[{"name":"LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, s\/n, R. Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-3967","authenticated-orcid":false,"given":"Joana A.","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, s\/n, R. Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-3432","authenticated-orcid":false,"given":"Maria Carmo","family":"Pereira","sequence":"additional","affiliation":[{"name":"LEPABE, Department of Chemical Engineering, Faculty of Engineering of the University of Porto, s\/n, R. Dr. Roberto Frias, 4200-465 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.jalz.2015.02.003","article-title":"2015 Alzheimer\u2019s disease facts and figures","volume":"11","author":"Association","year":"2015","journal-title":"Alzheimer\u2019s & Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/B978-0-12-385883-2.00008-4","article-title":"The genetics of Alzheimer\u2019s disease","volume":"107","author":"Bertram","year":"2012","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jalz.2019.01.010","article-title":"2019 Alzheimer\u2019s disease facts and figures","volume":"15","author":"Association","year":"2019","journal-title":"Alzheimer\u2019s & Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"926","DOI":"10.2174\/1570159X15666170116143743","article-title":"The Amyloid Cascade Hypothesis in Alzheimer\u2019s Disease: It\u2019s Time to Change Our Mind","volume":"15","author":"Ricciarelli","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/nature02264","article-title":"Folding proteins in fatal ways","volume":"426","author":"Selkoe","year":"2003","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.jmb.2003.11.048","article-title":"Structural Characterisation of Islet Amyloid Polypeptide Fibrils","volume":"335","author":"Serpell","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"451","DOI":"10.2119\/2007-00100.Irvine","article-title":"Protein aggregation in the brain: The molecular basis for Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"14","author":"Irvine","year":"2008","journal-title":"Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13827","DOI":"10.1074\/jbc.M110.199885","article-title":"Nature of the amyloid-beta monomer and the monomer-oligomer equilibrium","volume":"286","author":"Nag","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/1756285612461679","article-title":"Current and future treatments for Alzheimer\u2019s disease","volume":"6","author":"Yiannopoulou","year":"2013","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/S0140-6736(76)91936-X","article-title":"Selective loss of central cholinergic neurons in Alzheimer\u2019s disease","volume":"2","author":"Davies","year":"1976","journal-title":"Lancet (London, England)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1093\/brain\/99.3.459","article-title":"Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies","volume":"99","author":"Bowen","year":"1976","journal-title":"Brain A J. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer\u2019s disease drug-development pipeline: Few candidates, frequent failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimer\u2019s Res. & Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"168","DOI":"10.2165\/00023210-199504030-00002","article-title":"Tacrine-Induced Hepatotoxicity","volume":"4","author":"Balson","year":"1995","journal-title":"CNS Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Maia, M.A., and Sousa, E. (2019). BACE-1 and \u03b3-Secretase as Therapeutic Targets for Alzheimer\u2019s Disease. Pharmaceuticals (Basel), 12.","DOI":"10.3390\/ph12010041"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Andrade, S., Ramalho, M.J., Loureiro, J.A., and Pereira, M.D.C. (2019). Natural Compounds for Alzheimer\u2019s Disease Therapy: A Systematic Review of Preclinical and Clinical Studies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092313"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1016\/S0040-4020(02)00222-3","article-title":"Fluorous chemistry: From biphasic catalysis to a parallel chemical universe and beyond","volume":"58","author":"Gladysz","year":"2002","journal-title":"Tetrahedron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jfluchem.2013.10.013","article-title":"Synthesis and uses of fluorous and highly fluorinated macrocyclic and spherical molecules","volume":"157","author":"Yi","year":"2014","journal-title":"J. Fluor. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications of Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"J. Med Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/978-3-642-00477-3_14","article-title":"Targeting the brain--surmounting or bypassing the blood-brain barrier","volume":"197","author":"Potschka","year":"2010","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"709","DOI":"10.2217\/nnm.14.27","article-title":"Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies","volume":"9","author":"Loureiro","year":"2014","journal-title":"Nanomedicine (London)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.ejpb.2010.07.007","article-title":"Rivastigmine-loaded PLGA and PBCA nanoparticles: Preparation, optimization, characterization, in vitro and pharmacodynamic studies","volume":"76","author":"Joshi","year":"2010","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12951-018-0356-z","article-title":"Memantine loaded PLGA PEGylated nanoparticles for Alzheimer\u2019s disease: In vitro and in vivo characterization","volume":"16","author":"Ettcheto","year":"2018","journal-title":"J. Nanobiotechnology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.brainres.2008.01.039","article-title":"Poly(n-butylcyanoacrylate) nanoparticles coated with polysorbate 80 for the targeted delivery of rivastigmine into the brain to treat Alzheimer\u2019s disease","volume":"1200","author":"Wilson","year":"2008","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.nano.2011.03.008","article-title":"Nanotechnologies for Alzheimer\u2019s disease: Diagnosis, therapy, and safety issues","volume":"7","author":"Brambilla","year":"2011","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.nano.2009.11.007","article-title":"Pharmacological and toxicological target organelles and safe use of single-walled carbon nanotubes as drug carriers in treating Alzheimer disease","volume":"6","author":"Yang","year":"2010","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0169-409X(00)00122-8","article-title":"Nanoparticulate systems for brain delivery of drugs","volume":"47","author":"Kreuter","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.jddst.2019.03.022","article-title":"Nanotechnology approaches for enhanced CNS delivery in treating Alzheimer\u2019s disease","volume":"51","author":"Arya","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.colsurfb.2016.04.041","article-title":"Cellular uptake of PLGA nanoparticles targeted with anti-amyloid and anti-transferrin receptor antibodies for Alzheimer\u2019s disease treatment","volume":"145","author":"Loureiro","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1080\/10717544.2018.1428243","article-title":"Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer\u2019s disease","volume":"25","author":"Karthivashan","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bpc.2008.06.010","article-title":"Influence of fluorinated and hydrogenated nanoparticles on the structure and fibrillogenesis of amyloid beta-peptide","volume":"137","author":"Rocha","year":"2008","journal-title":"Biophys. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1002\/cbic.201000237","article-title":"Controlling Amyloid-\u03b2 Peptide(1\u201342) Oligomerization and Toxicity by Fluorinated Nanoparticles","volume":"11","author":"Pereira","year":"2010","journal-title":"ChemBioChem"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.2174\/1381612821666150130120358","article-title":"The Potential Effect of Fluorinated Compounds in the Treatment of Alzheimer\u2019s Disease","volume":"21","author":"Gomes","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev.pharmtox.41.1.443","article-title":"Metabolism of fluorine-containing drugs","volume":"41","author":"Park","year":"2001","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11797","DOI":"10.1002\/chem.201901840","article-title":"Fluorine-Containing Drugs Approved by the FDA in 2018","volume":"25","author":"Mei","year":"2019","journal-title":"Chem.\u2014A Eur. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5822","DOI":"10.1021\/acs.jmedchem.7b01788","article-title":"Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design","volume":"61","author":"Meanwell","year":"2018","journal-title":"J. Med Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/bk-1996-0639.ch001","article-title":"Recent Advances in the Biomedicinal Chemistry of Fluorine-Containing Compounds","volume":"Volume 639","author":"Kirk","year":"1996","journal-title":"Biomedical Frontiers of Fluorine Chemistry"},{"key":"ref_37","first-page":"645","article-title":"Some influences of fluorine in bioorganic chemistry","volume":"7","author":"Rzepa","year":"1997","journal-title":"Chem. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/128_2011_270","article-title":"Biology of fluoro-organic compounds","volume":"308","author":"Zhang","year":"2012","journal-title":"Top. Curr. Chem."},{"key":"ref_39","first-page":"1043","article-title":"Aspects of the medicinal chemistry of fluoroorganic compounds. Part, I","volume":"45","author":"Resnati","year":"1990","journal-title":"Farm. (Soc. Chim. Ital. 1989)"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/cr4002879","article-title":"Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001\u20132011)","volume":"114","author":"Wang","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.jfluchem.2006.05.006","article-title":"Recent advances (1995\u20132005) in fluorinated pharmaceuticals based on natural products","volume":"127","year":"2006","journal-title":"J. Fluor. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1080\/14756360701425014","article-title":"The role of fluorine in medical chemistry","volume":"22","author":"Shah","year":"2005","journal-title":"J. Enzime Inhib. Med Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jfluchem.2018.11.002","article-title":"Recent progress in the strategic incorporation of fluorine into medicinally active compounds","volume":"217","author":"Haranahalli","year":"2019","journal-title":"J. Fluor. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1126\/science.1131943","article-title":"Fluorine in pharmaceuticals: Looking beyond intuition","volume":"317","author":"Muller","year":"2007","journal-title":"Science (New York)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.2174\/156802606777951046","article-title":"Fluorinated Molecules as Drugs and Imaging Agents in the CNS","volume":"6","author":"Shengguo","year":"2006","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1021\/acsmedchemlett.9b00235","article-title":"The Dark Side of Fluorine","volume":"10","author":"Pan","year":"2019","journal-title":"ACS Medicinal Chem. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1093\/cid\/ciq188","article-title":"Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy","volume":"52","author":"Wermers","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nature02265","article-title":"Therapeutic approaches to protein-misfolding diseases","volume":"426","author":"Cohen","year":"2003","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1146\/annurev.bioeng.4.092801.094202","article-title":"Peptide aggregation in neurodegenerative disease","volume":"4","author":"Murphy","year":"2002","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1039\/b818687a","article-title":"Protein stability modulated by a conformational effector: Effects of trifluoroethanol on bovine serum albumin","volume":"11","author":"Carrotta","year":"2009","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S1570-9639(02)00461-2","article-title":"Change and stabilization of the amyloid-\u03b2(1\u201340) secondary structure by fluorocompounds","volume":"1645","author":"Vieira","year":"2003","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Proteins Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1007\/s00726-014-1819-7","article-title":"Impact of fluorination on proteolytic stability of peptides: A case study with alpha-chymotrypsin and pepsin","volume":"46","author":"Asante","year":"2014","journal-title":"Amino Acids"},{"key":"ref_53","first-page":"157","article-title":"Proteolytically stable peptides by incorporation of alpha-Tfm amino acids","volume":"3","author":"Koksch","year":"1997","journal-title":"J. Pept. Sci. An Off. Publ. Eur. Pept. Soc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1039\/C1CS15241F","article-title":"Fluorinated amino acids: Compatibility with native protein structures and effects on protein-protein interactions","volume":"41","author":"Salwiczek","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4069","DOI":"10.1021\/jp300284u","article-title":"Local control of the cis-trans isomerization and backbone dihedral angles in peptides using trifluoromethylated pseudoprolines","volume":"116","author":"Feytens","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1039\/C3TB21483D","article-title":"Fluorinated beta-sheet breaker peptides","volume":"2","author":"Loureiro","year":"2014","journal-title":"J. Mater. Chem. B"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/bip.22670","article-title":"(R)-\u03b1-trifluoromethylalanine containing short peptide in the inhibition of amyloid peptide fibrillation","volume":"104","author":"Botz","year":"2015","journal-title":"Biopolymers"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5377","DOI":"10.1021\/bi0601104","article-title":"Organofluorine Inhibitors of Amyloid Fibrillogenesis","volume":"45","author":"Abid","year":"2006","journal-title":"Biochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6931","DOI":"10.1016\/j.bmcl.2009.10.066","article-title":"Effect of chirality of small molecule organofluorine inhibitors of amyloid self-assembly on inhibitor potency","volume":"19","author":"Sood","year":"2009","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1016\/j.bmcl.2011.02.012","article-title":"Disassembly of preformed amyloid beta fibrils by small organofluorine molecules","volume":"21","author":"Sood","year":"2011","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7185","DOI":"10.1074\/jbc.273.13.7185","article-title":"Inhibition of Alzheimer \u03b2-fibrillogenesis by melatonin","volume":"273","author":"Pappolla","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_62","unstructured":"Elmaleh, D.R., and Shoup, T. (2010). Cromolyn Derivatives and Related Methods of Imaging and Treatment. (WO 2010088455A2)."},{"key":"ref_63","unstructured":"Reed, M.A., Yadav, A., Banfield, S.C., and Barden, C.J. (2012). Anti-amyloid Compounds and Methods. (WO 2012119035A1)."},{"key":"ref_64","unstructured":"Horwell, D., and Scopes, D. (2011). Compounds. (WO 2011144577A1)."},{"key":"ref_65","unstructured":"Horwell, D.C., and Scopes, D.I.C. (2011). Compounds. (WO 2011144578A1)."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1021\/bm034151g","article-title":"Influence of Hydrophobic Teflon Particles on the Structure of Amyloid \u03b2-Peptide","volume":"4","author":"Giacomelli","year":"2003","journal-title":"Biomacromolecules"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2174\/157340708786305970","article-title":"Chemistry of Small Molecule Inhibitors in Self-Assembly of Alzheimers Disease Related Amyloid-Beta Peptide","volume":"4","author":"Bela","year":"2008","journal-title":"Curr. Bioact. Compd."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jmgm.2016.11.013","article-title":"The effects of fluorine substitution on the chemical properties and inhibitory capacity of Donepezil anti-Alzheimer drug; density functional theory and molecular docking calculations","volume":"71","author":"Khosravan","year":"2017","journal-title":"J. Mol. Graph. Model."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.bmcl.2018.12.049","article-title":"New evolutions in the BACE1 inhibitor field from 2014 to 2018","volume":"29","author":"Hsiao","year":"2019","journal-title":"Bioorganic & Med. Chem. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1093\/hmg\/10.12.1317","article-title":"BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: Implications for Alzheimer\u2019s disease therapeutics","volume":"10","author":"Roberds","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1021\/jm061242y","article-title":"Design, Synthesis, and Crystal Structure of Hydroxyethyl Secondary Amine-Based Peptidomimetic Inhibitors of Human \u03b2-Secretase","volume":"50","author":"Maillard","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"14772","DOI":"10.1002\/chem.201102078","article-title":"Design, Synthesis, and Biological Evaluation of Novel Fluorinated Ethanolamines","volume":"17","author":"Fustero","year":"2011","journal-title":"Chem.\u2014A Eur. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1021\/jm800219f","article-title":"The Many Roles for Fluorine in Medicinal Chemistry","volume":"51","author":"Hagmann","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/B610213C","article-title":"Fluorine in medicinal chemistry","volume":"37","author":"Purser","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1523\/JNEUROSCI.4129-14.2015","article-title":"The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A\u03b2 Pharmacodynamic Responses in Mice, Dogs, and Humans","volume":"35","author":"May","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_76","unstructured":"Green, S.J., Hembre, E.J., Mergott, D.J., Shi, Y., Watson, B.M., and Winneroski Jr., L.L. (2014). BACE Inhibitors. (WO 2014204730)."},{"key":"ref_77","unstructured":"Michael, D., Simon, R., Richards, J., and Sanderson, A.J. (2016). Tetrahydrofurane-Fused Aminohydrothiazine Derivatives which are Useful in the Treatment of Alzheimer\u2019s Disease. (WO 2016176118A1)."},{"key":"ref_78","unstructured":"Coates, D.A., and Hembre, E.J. (2017). -[3-[2-amino-5-(1,1-difluoroethyl) -4,4a,5,7-tetrahydrofuro [3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide and its (4ar,5s,7as) isomer as a selective bace1 inhibitor for treating e.g., alzheimer\u2019s disease. (WO 2017200863A1)."},{"key":"ref_79","unstructured":"Mergott, D.J., and Willis, B.A. (2018). Combination therapy of BACE-1 inhibitor and anti-N3PGLU abeta antibody. (WO 2018034977)."},{"key":"ref_80","unstructured":"Dimopoulos, P., Hall, A., Kita, Y., Madin, A., and Shuker, N.L. (2012). Fused aminodihydrothiaziine derivatives. (WO \/2012\/093148)."},{"key":"ref_81","unstructured":"Hall, A., Farthing, C.N., Castro, P., and Fused, J. (2012). Used aminodihydrothiazine derivatives useful as bace inhibitors. (WO \/2012\/098213)."},{"key":"ref_82","unstructured":"Kusakabe, K., Tadano, G., Komano, K., Fuchino, K., and Nakahara, K. (2015). Dihydrothiazine and dihydrooxazine derivatives having BACE1 inhibitory activity. (WO \/2015\/156421)."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1016\/j.bmcl.2013.05.003","article-title":"BACE1 inhibitors: A head group scan on a series of amides","volume":"23","author":"Woltering","year":"2013","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_84","unstructured":"Lueoend, R.M., Machauer, R., Rueeger, H., and Veenstra, S.J. (2013). 2 -amino-4 -(pyridin-2-yl)-5, 6-dihidro-4H-1, 3-oxazine derivatives and their use as BACE-1 and\/or BACE\u20142 inhibitors. (WO \/2013\/027188)."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.bmcl.2018.01.056","article-title":"Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation","volume":"28","author":"Low","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1021\/acs.jmedchem.8b00644","article-title":"Design, Synthesis, and Biological Evaluation of Novel 7-[(3aS,7aS)-3a-Aminohexahydropyrano [3,4-c]pyrrol-2(3H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens","volume":"61","author":"Odagiri","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3980","DOI":"10.1021\/jm400225m","article-title":"\u03b2-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer\u2019s Disease","volume":"56","author":"Hilpert","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1021\/acsmedchemlett.5b00281","article-title":"Novel Fluorinated 8-Hydroxyquinoline Based Metal Ionophores for Exploring the Metal Hypothesis of Alzheimer\u2019s Disease","volume":"6","author":"Liang","year":"2015","journal-title":"ACS Med. Chem. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2989\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:07Z","timestamp":1760364547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,23]]},"references-count":88,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21082989"],"URL":"https:\/\/doi.org\/10.3390\/ijms21082989","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2020,4,23]]}}}