{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T14:31:51Z","timestamp":1792420311588,"version":"4.5.0"},"reference-count":119,"publisher":"Elsevier BV","issue":"10","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T00:00:00Z","timestamp":1693872000000},"content-version":"am","delay-in-days":339,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"publisher","award":["W81XWH210053"],"award-info":[{"award-number":["W81XWH210053"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmn.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Drug Discovery Today"],"published-print":{"date-parts":[[2022,10]]},"DOI":"10.1016\/j.drudis.2022.07.007","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T17:45:43Z","timestamp":1658252743000},"page":"103322","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":56,"title":["Pivotal role of nitrogen heterocycles in Alzheimer\u2019s disease drug discovery"],"prefix":"10.1016","volume":"27","author":[{"given":"Shikha","family":"Kumari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnaiah","family":"Maddeboina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinda Devi","family":"Bachu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai H.S.","family":"Boddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul C.","family":"Trippier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit K.","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.drudis.2022.07.007_b0005","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The neuropathological diagnosis of Alzheimer's disease","volume":"14","author":"DeTure","year":"2019","journal-title":"Mol Neurodegener"},{"key":"10.1016\/j.drudis.2022.07.007_b0010","doi-asserted-by":"crossref","unstructured":"Global, regional, and national burden of Alzheimer's disease and other dementias, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18(1):88\u2013106. doi: 10.1016\/s1474-4422(18)30403-4.","DOI":"10.1016\/S1474-4422(18)30403-4"},{"key":"10.1016\/j.drudis.2022.07.007_b0015","doi-asserted-by":"crossref","first-page":"17602","DOI":"10.1039\/D0RA00663G","volume":"10","author":"Mishra","year":"2020","journal-title":"RSC Adv"},{"key":"10.1016\/j.drudis.2022.07.007_b0020","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1016\/j.drudis.2020.09.025","article-title":"Smart treatment strategies for alleviating tauopathy and neuroinflammation to improve clinical outcome in Alzheimer's disease","volume":"25","author":"Tatiparti","year":"2020","journal-title":"Drug Discov Today"},{"key":"10.1016\/j.drudis.2022.07.007_b0025","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.disamonth.2010.06.001","article-title":"Alzheimer disease","volume":"56","author":"Castellani","year":"2010","journal-title":"Dis Mon"},{"key":"10.1016\/j.drudis.2022.07.007_b0030","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3389\/fnins.2019.00446","article-title":"Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses","volume":"13","author":"Chen","year":"2019","journal-title":"Front Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0035","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.drudis.2020.04.002","article-title":"The current landscape in Alzheimer's disease research and drug discovery","volume":"25","author":"Devenish","year":"2020","journal-title":"Drug Discov Today"},{"key":"10.1016\/j.drudis.2022.07.007_b0040","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1177\/2042098617750555","article-title":"An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine","volume":"9","author":"Khoury","year":"2018","journal-title":"Ther Adv Drug Saf"},{"key":"10.1016\/j.drudis.2022.07.007_b0045","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/B978-0-12-804766-8.00013-3","article-title":"Alzheimer's disease","volume":"167","author":"Soria Lopez","year":"2019","journal-title":"Handb Clin Neurol"},{"key":"10.1016\/j.drudis.2022.07.007_b0050","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1001\/jama.1994.03510370044030","article-title":"Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease","volume":"271","author":"Watkins","year":"1994","journal-title":"JAMA"},{"key":"10.1016\/j.drudis.2022.07.007_b0055","first-page":"1479","article-title":"Cholinesterase inhibitors as Alzheimer's therapeutics (Review)","volume":"20","author":"Sharma","year":"2019","journal-title":"Mol Med Rep"},{"key":"10.1016\/j.drudis.2022.07.007_b0060","unstructured":"Chaudhary A, Maurya PK, Yadav BS, Singh S, Mani A. Current Therapeutic Targets for Alzheimer. Review. J Biomed."},{"key":"10.1016\/j.drudis.2022.07.007_b0065","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jfma.2015.04.001","article-title":"Current and novel therapeutic molecules and targets in Alzheimer's disease","volume":"115","author":"Kumar","year":"2016","journal-title":"J Formos Med Assoc"},{"key":"10.1016\/j.drudis.2022.07.007_b0070","doi-asserted-by":"crossref","first-page":"12290","DOI":"10.1021\/acs.jmedchem.0c00530","article-title":"Amide Bond Bioisosteres: Strategies, Synthesis, and Successes","volume":"63","author":"Kumari","year":"2020","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0075","doi-asserted-by":"crossref","first-page":"S145","DOI":"10.3233\/JAD-190744","article-title":"Current and Emerging Pharmacological Targets for the Treatment of Alzheimer\u2019s Disease","volume":"72","author":"Morsy","year":"2019","journal-title":"J Alzheimer's Dis"},{"key":"10.1016\/j.drudis.2022.07.007_b0080","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1021\/acs.jmedchem.8b01530","article-title":"Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer\u2019s Disease","volume":"62","author":"Morsy","year":"2019","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0085","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.bmc.2005.09.011","article-title":"The benefits of the multi-target approach in drug design and discovery","volume":"14","author":"Espinoza-Fonseca","year":"2006","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0090","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1021\/jm3015926","article-title":"Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers","volume":"56","author":"Trippier","year":"2013","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0095","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.2174\/1381612822666160518141650","article-title":"Heterocyclic Scaffolds for the Treatment of Alzheimer\u2019s Disease","volume":"22","author":"Annamaria","year":"2016","journal-title":"Curr Pharm Des"},{"key":"10.1016\/j.drudis.2022.07.007_b0100","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.4103\/1673-5374.213541","article-title":"Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer's disease therapy. Invited Review","volume":"12","author":"Hiremathad","year":"2017","journal-title":"Neural Regener Res"},{"key":"10.1016\/j.drudis.2022.07.007_b0105","doi-asserted-by":"crossref","first-page":"e12050","DOI":"10.1002\/trc2.12050","article-title":"Alzheimer's disease drug development pipeline: 2020","volume":"6","author":"Cummings","year":"2020","journal-title":"Alzheimer's & Dementia: Translat Res Clin Intervent"},{"key":"10.1016\/j.drudis.2022.07.007_b0110","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12929-019-0609-7","article-title":"Clinical trials of new drugs for Alzheimer disease","volume":"27","author":"Huang","year":"2020","journal-title":"J Biomed Sci"},{"key":"10.1016\/j.drudis.2022.07.007_b0115","doi-asserted-by":"crossref","first-page":"101318","DOI":"10.1016\/j.arr.2021.101318","article-title":"Therapy for Alzheimer's disease: Missing targets and functional markers?","volume":"68","author":"Stoiljkovic","year":"2021","journal-title":"Ageing Res Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0120","article-title":"Bromide: An Organic Intermediate for Synthesis of Five- and Six-Membered Bioactive","author":"Jangid","year":"2019","journal-title":"Heterocycles"},{"key":"10.1016\/j.drudis.2022.07.007_b0125","doi-asserted-by":"crossref","first-page":"44247","DOI":"10.1039\/D0RA09198G","article-title":"Prescribed drugs containing nitrogen heterocycles: an overview","volume":"10","author":"Heravi","year":"2020","journal-title":"RSC Adv"},{"key":"10.1016\/j.drudis.2022.07.007_b0130","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.2174\/1871520620666200705214917","article-title":"Nitrogen-Containing Heterocycles as Anticancer Agents: An Overview","volume":"20","author":"Lang","year":"2020","journal-title":"Anticancer Agents Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0135","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.3390\/molecules25081909","article-title":"A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications","volume":"25","author":"Kerru","year":"2020","journal-title":"Molecules"},{"key":"10.1016\/j.drudis.2022.07.007_b0140","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.ejmech.2019.07.059","article-title":"Triazole derivatives as inhibitors of Alzheimer's disease: Current developments and structure-activity relationships","volume":"180","author":"Xu","year":"2019","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0145","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1002\/slct.202100332","article-title":"Pyridine Derivatives as Biologically Active Precursors; Organics and Selected Coordination Complexes","volume":"6","author":"Khan","year":"2021","journal-title":"ChemistrySelect"},{"key":"10.1016\/j.drudis.2022.07.007_b0150","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s43094-020-00165-4","article-title":"Medicinal attributes of pyridine scaffold as anticancer targeting agents","volume":"7","author":"Mohamed","year":"2021","journal-title":"Future J Pharm Sci"},{"key":"10.1016\/j.drudis.2022.07.007_b0155","unstructured":"Altaf AA, Shahzad A, Gul Z, et al. A Review on the Medicinal Importance of Pyridine Derivatives. 2015."},{"key":"10.1016\/j.drudis.2022.07.007_b0160","doi-asserted-by":"crossref","first-page":"115455","DOI":"10.1016\/j.bmc.2020.115455","article-title":"Optimization and biological evaluation of imidazopyridine derivatives as a novel scaffold for \u03b3-secretase modulators with oral efficacy against cognitive deficits in Alzheimer's disease model mice","volume":"28","author":"Sekioka","year":"2020","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0165","doi-asserted-by":"crossref","first-page":"571","DOI":"10.2174\/156720507783018299","article-title":"gamma-Secretase modulators","volume":"4","author":"Wolfe","year":"2007","journal-title":"Curr Alzheimer Res"},{"key":"10.1016\/j.drudis.2022.07.007_b0170","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1471-4159.2011.07501.x","article-title":"\u03b3-Secretase inhibitors and modulators for Alzheimer's disease","volume":"120","author":"Wolfe","year":"2012","journal-title":"J Neurochem"},{"key":"10.1016\/j.drudis.2022.07.007_b0175","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1021\/acs.jmedchem.6b01173","article-title":"Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer's Disease","volume":"60","author":"Rombouts","year":"2017","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0180","doi-asserted-by":"crossref","first-page":"975","DOI":"10.2967\/jnumed.116.185199","article-title":"Preclinical Evaluation of (18)F-JNJ64349311, a Novel PET Tracer for Tau Imaging","volume":"58","author":"Declercq","year":"2017","journal-title":"J Nucl Med"},{"key":"10.1016\/j.drudis.2022.07.007_b0185","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/s41380-018-0342-8","article-title":"Tau PET imaging in neurodegenerative tauopathies-still a challenge","volume":"24","author":"Leuzy","year":"2019","journal-title":"Mol Psychiatry"},{"key":"10.1016\/j.drudis.2022.07.007_b0190","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1007\/s00259-020-05156-4","article-title":"Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework","volume":"48","author":"Bischof","year":"2021","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"10.1016\/j.drudis.2022.07.007_b0195","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1007\/s00259-019-04397-2","article-title":"Discovery and preclinical characterization of [(18)F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer's disease and other tauopathies","volume":"46","author":"Kroth","year":"2019","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"10.1016\/j.drudis.2022.07.007_b0200","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ejmech.2019.02.005","article-title":"Tacrines for Alzheimer's disease therapy. III. The PyridoTacrines","volume":"166","author":"de Los","year":"2019","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0205","doi-asserted-by":"crossref","first-page":"332","DOI":"10.2174\/138920008784220619","article-title":"Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease","volume":"9","author":"Patocka","year":"2008","journal-title":"Curr Drug Metab"},{"key":"10.1016\/j.drudis.2022.07.007_b0210","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1586\/14737175.8.11.1703","article-title":"Cholinergic system during the progression of Alzheimer's disease: therapeutic implications","volume":"8","author":"Mufson","year":"2008","journal-title":"Expert Rev Neurother"},{"key":"10.1016\/j.drudis.2022.07.007_b0215","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/1570159X13666150716165726","article-title":"Alzheimer's disease: Targeting the Cholinergic System","volume":"14","author":"Ferreira-Vieira","year":"2016","journal-title":"Curr Neuropharmacol"},{"key":"10.1016\/j.drudis.2022.07.007_b0220","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1517\/14656566.2011.520702","article-title":"Current perspectives on pharmacotherapy of Alzheimer's disease","volume":"12","author":"Chopra","year":"2011","journal-title":"Expert Opin Pharmacother"},{"key":"10.1016\/j.drudis.2022.07.007_b0225","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1021\/jm000979z","article-title":"Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of (4)N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines","volume":"44","author":"Easmon","year":"2001","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0230","first-page":"202784","article-title":"Significance and Biological Importance of Pyrimidine in the Microbial World","volume":"2014","author":"Sharma","year":"2014","journal-title":"Int J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0235","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1039\/C1MD00074H","article-title":"Are pyridazines privileged structures?","volume":"2","author":"Wermuth","year":"2011","journal-title":"MedChemComm"},{"key":"10.1016\/j.drudis.2022.07.007_b0240","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/sj.bjp.0704911","article-title":"A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro","volume":"137","author":"Nakagami","year":"2002","journal-title":"Br J Pharmacol"},{"key":"10.1016\/j.drudis.2022.07.007_b0245","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbr.2010.01.044","article-title":"RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo","volume":"210","author":"O'Hare","year":"2010","journal-title":"Behav Brain Res"},{"key":"10.1016\/j.drudis.2022.07.007_b0250","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1021\/acs.chemrestox.8b00210","article-title":"Synthesis and Structure Activity Relationship of Pyridazine-Based Inhibitors for Elucidating the Mechanism of Amyloid Inhibition","volume":"31","author":"Kalhor","year":"2018","journal-title":"Chem Res Toxicol"},{"key":"10.1016\/j.drudis.2022.07.007_b0255","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ejmech.2018.02.063","article-title":"Design, synthesis, and biological evaluation of compounds with a new scaffold as anti-neuroinflammatory agents for the treatment of Alzheimer's disease","volume":"149","author":"Fang","year":"2018","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0260","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1021\/acschemneuro.6b00125","article-title":"Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's Disease Models","volume":"7","author":"Zhou","year":"2016","journal-title":"ACS Chem Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0265","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.bbadis.2009.07.005","article-title":"Mitochondrial permeability transition pore in Alzheimer's disease: cyclophilin D and amyloid beta","volume":"1802","author":"Du","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"10.1016\/j.drudis.2022.07.007_b0270","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.redox.2018.09.001","article-title":"Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease","volume":"19","author":"P\u00e9rez","year":"2018","journal-title":"Redox Biol"},{"key":"10.1016\/j.drudis.2022.07.007_b0275","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ejmech.2018.07.068","article-title":"Pyrazinyl ureas revisited: 1-(3-(Benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea, a new blocker of Abeta-induced mPTP opening for Alzheimer's disease","volume":"157","author":"Elkamhawy","year":"2018","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0280","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ejmech.2017.12.045","article-title":"Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of A\u03b2-induced mitochondrial dysfunction in Alzheimer's disease","volume":"144","author":"Elkamhawy","year":"2018","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0285","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.ejmech.2017.09.043","article-title":"Synthesis and evaluation of new pyridyl\/pyrazinyl thiourea derivatives: Neuroprotection against amyloid-\u03b2-induced toxicity","volume":"141","author":"Park","year":"2017","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0290","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/jnc.15003","article-title":"Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function","volume":"155","author":"Cheng","year":"2020","journal-title":"J Neurochem"},{"key":"10.1016\/j.drudis.2022.07.007_b0295","doi-asserted-by":"crossref","first-page":"17042","DOI":"10.1523\/JNEUROSCI.1836-13.2013","article-title":"Mitochondrial alterations near amyloid plaques in an Alzheimer's disease mouse model","volume":"33","author":"Xie","year":"2013","journal-title":"J Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0300","article-title":"Improved mitochondrial function in brain aging and Alzheimer disease \u2013 the new mechanism of action of the old metabolic enhancer piracetam. Review","volume":"4","author":"Leuner","year":"2010","journal-title":"Front Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0305","doi-asserted-by":"crossref","first-page":"451.e5","DOI":"10.1016\/j.genhosppsych.2012.05.009","article-title":"Piracetam treatment in patients with cognitive impairment","volume":"35","author":"Rao","year":"2013","journal-title":"Gen Hosp Psychiatry"},{"key":"10.1016\/j.drudis.2022.07.007_b0310","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-03085-3","article-title":"Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes","volume":"9","author":"Ye","year":"2018","journal-title":"Nature Commun"},{"key":"10.1016\/j.drudis.2022.07.007_b0315","doi-asserted-by":"crossref","first-page":"15213","DOI":"10.1039\/D1RA00341K","article-title":"Piperazine based antimicrobial polymers: a review","volume":"11","author":"Jalageri","year":"2021","journal-title":"RSC Adv"},{"key":"10.1016\/j.drudis.2022.07.007_b0320","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.bmc.2015.03.055","article-title":"Design and synthesis of piperazine derivatives as a novel class of \u03b3-secretase modulators that selectively lower A\u03b2\u2084\u2082 production","volume":"23","author":"Takai","year":"2015","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0325","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1016\/j.bmc.2016.06.027","article-title":"Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-\u03b2-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer's disease","volume":"24","author":"Mishra","year":"2016","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0330","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4062\/biomolther.2017.189","article-title":"The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents","volume":"26","author":"Shin","year":"2018","journal-title":"Biomol Ther (Seoul)"},{"key":"10.1016\/j.drudis.2022.07.007_b0335","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1002\/jnr.20025","article-title":"Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro","volume":"75","author":"Ono","year":"2004","journal-title":"J Neurosci Res"},{"key":"10.1016\/j.drudis.2022.07.007_b0340","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.neuropharm.2003.09.005","article-title":"Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats","volume":"46","author":"Shachar","year":"2004","journal-title":"Neuropharmacology"},{"key":"10.1016\/j.drudis.2022.07.007_b0345","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2174\/1573406411006030123","article-title":"Dimethyl-carbamic acid 2,3-Bis-Dimethylcarbamoyloxy-6-(4-Ethyl-Piperazine-1-Carbonyl)-phenyl ester: a novel multi-target therapeutic approach to neuroprotection","volume":"6","author":"Lecanu","year":"2010","journal-title":"Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0350","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.ejmech.2016.09.057","article-title":"Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease","volume":"125","author":"Mishra","year":"2017","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0355","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ejmech.2018.08.017","article-title":"Recent advancement of piperidine moiety in treatment of cancer- A review","volume":"157","author":"Goel","year":"2018","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0360","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/med.21622","article-title":"BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease","volume":"40","author":"Moussa-Pacha","year":"2020","journal-title":"Med Res Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0365","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.4155\/fmc-2019-0163","article-title":"An overview of glutaminyl cyclase inhibitors for Alzheimer\u2019s disease","volume":"11","author":"Coimbra","year":"2019","journal-title":"Future Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0370","doi-asserted-by":"crossref","first-page":"8076","DOI":"10.1021\/acs.jmedchem.1c00489","article-title":"Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor","volume":"64","author":"McKinzie","year":"2021","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0375","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1021\/acsmedchemlett.5b00483","article-title":"Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors","volume":"7","author":"Costanzo","year":"2016","journal-title":"ACS Med Chem Lett"},{"key":"10.1016\/j.drudis.2022.07.007_b0380","doi-asserted-by":"crossref","first-page":"103589","DOI":"10.1016\/j.bioorg.2020.103589","article-title":"Design, synthesis and evaluation of pyrazole bearing \u03b1-aminophosphonate derivatives as potential acetylcholinesterase inhibitors against Alzheimer's disease","volume":"96","author":"Shaikh","year":"2020","journal-title":"Bioorg Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0385","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.2174\/138955708786369582","article-title":"Antioxidant therapy in Alzheimer's disease: theory and practice","volume":"8","author":"Aliev","year":"2008","journal-title":"Mini Rev Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0390","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1021\/cr60168a001","article-title":"The Chemistry of Sultones and Sultams","volume":"54","author":"Mustafa","year":"1954","journal-title":"Chem Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0395","doi-asserted-by":"crossref","first-page":"103037","DOI":"10.1016\/j.arabjc.2021.103037","article-title":"Recent developments of synthesis and biological activity of sultone scaffolds in medicinal chemistry","volume":"14","author":"Xu","year":"2021","journal-title":"Arab J Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0400","doi-asserted-by":"crossref","first-page":"111598","DOI":"10.1016\/j.ejmech.2019.111598","article-title":"Discovery of \u03b4-sultone-fused pyrazoles for treating Alzheimer's disease: Design, synthesis, biological evaluation and SAR studies","volume":"181","author":"Xu","year":"2019","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0405","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.neuroscience.2015.04.039","article-title":"Butyrylcholinesterase-knockout reduces brain deposition of fibrillar \u03b2-amyloid in an Alzheimer mouse model","volume":"298","author":"Reid","year":"2015","journal-title":"Neuroscience"},{"key":"10.1016\/j.drudis.2022.07.007_b0410","doi-asserted-by":"crossref","first-page":"112273","DOI":"10.1016\/j.ejmech.2020.112273","article-title":"The structure-based optimization of \u03b4-sultone-fused pyrazoles as selective BuChE inhibitors","volume":"201","author":"Zhang","year":"2020","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0415","first-page":"1","article-title":"A Historical Perspective","author":"Tautomerism","year":"2016","journal-title":"Tautomerism"},{"key":"10.1016\/j.drudis.2022.07.007_b0420","series-title":"Comprehensive Heterocyclic Chemistry III","first-page":"143","article-title":"4.02 \u2013 Imidazoles","author":"Xi","year":"2008"},{"key":"10.1016\/j.drudis.2022.07.007_b0425","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1002\/med.21290","article-title":"Comprehensive review in current developments of imidazole-based medicinal chemistry","volume":"34","author":"Zhang","year":"2014","journal-title":"Med Res Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0430","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.2147\/DDDT.S307113","article-title":"Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction","volume":"15","author":"Alghamdi","year":"2021","journal-title":"Drug Des Devel Ther"},{"key":"10.1016\/j.drudis.2022.07.007_b0435","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fnins.2018.00025","article-title":"Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease","volume":"12","author":"Kametani","year":"2018","journal-title":"Front Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0440","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol Sin"},{"key":"10.1016\/j.drudis.2022.07.007_b0445","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nature11060","article-title":"Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-\u03b2","volume":"485","author":"Nussbaum","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.drudis.2022.07.007_b0450","unstructured":"Heiser U, et al., Inventor. Heterocyclic derivatives as inhibitors of glutaminyl cyclase. Patent application PCT\/EP2010\/063341. 2011."},{"key":"10.1016\/j.drudis.2022.07.007_b0455","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1124\/jpet.117.240614","article-title":"Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer's Disease-Studies on Relation to Effective Target Occupancy","volume":"362","author":"Hoffmann","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"key":"10.1016\/j.drudis.2022.07.007_b0460","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13195-021-00882-9","article-title":"Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD","volume":"13","author":"Vijverberg","year":"2021","journal-title":"Alzheimers Res Ther"},{"key":"10.1016\/j.drudis.2022.07.007_b0465","doi-asserted-by":"crossref","first-page":"6664","DOI":"10.1021\/acs.jmedchem.7b00648","article-title":"Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer\u2019s Disease","volume":"60","author":"Li","year":"2017","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0470","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/nm.1872","article-title":"Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology","volume":"14","author":"Schilling","year":"2008","journal-title":"Nat Med"},{"key":"10.1016\/j.drudis.2022.07.007_b0475","doi-asserted-by":"crossref","DOI":"10.1590\/0001-3765201820180751","article-title":"Strategies Towards the Synthesis of N2-Substituted 1,2,3-Triazoles","volume":"91","author":"Souza","year":"2019","journal-title":"Anais da Academia Brasileira de Ci\u00eancias"},{"key":"10.1016\/j.drudis.2022.07.007_b0480","doi-asserted-by":"crossref","first-page":"5715","DOI":"10.1016\/S0040-4020(01)00485-9","article-title":"Aromaticity indices revisited: refinement and application to certain five-membered ring heterocycles","volume":"57","author":"Kotelevskii","year":"2001","journal-title":"Tetrahedron"},{"key":"10.1016\/j.drudis.2022.07.007_b0485","doi-asserted-by":"crossref","first-page":"112652","DOI":"10.1016\/j.ejmech.2020.112652","article-title":"An insight on medicinal attributes of 1,2,4-triazoles","volume":"205","author":"Aggarwal","year":"2020","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0490","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/14756360903524304","article-title":"Pharmacological significance of triazole scaffold","volume":"26","author":"Kharb","year":"2011","journal-title":"J Enzyme Inhib Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0495","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1016\/j.drudis.2017.05.014","article-title":"The 1,2,3-triazole ring as a bioisostere in medicinal chemistry","volume":"22","author":"Bonandi","year":"2017","journal-title":"Drug Discov Today"},{"key":"10.1016\/j.drudis.2022.07.007_b0500","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.brainres.2015.12.016","article-title":"Pharmacological properties of a novel and potent \u03b3-secretase modulator as a therapeutic option for the treatment of Alzheimer's disease","volume":"1633","author":"Murakami","year":"2016","journal-title":"Brain Res"},{"key":"10.1016\/j.drudis.2022.07.007_b0505","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.bioorg.2018.11.038","article-title":"Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation","volume":"84","author":"Yazdani","year":"2019","journal-title":"Bioorg Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0510","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.bioorg.2018.01.017","article-title":"Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer's disease","volume":"77","author":"Iraji","year":"2018","journal-title":"Bioorg Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0515","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.ejmech.2017.09.057","article-title":"Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer's disease","volume":"141","author":"Iraji","year":"2017","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0520","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1021\/acs.chemrev.8b00564","article-title":"Tetrazoles via Multicomponent Reactions","volume":"119","author":"Neochoritis","year":"2019","journal-title":"Chem Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0525","doi-asserted-by":"crossref","first-page":"91","DOI":"10.4155\/fmc-2019-0288","article-title":"Bioisosteres in drug discovery: focus on tetrazole","volume":"12","author":"Zou","year":"2019","journal-title":"Future Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0530","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1021\/acs.jmedchem.5b01963","article-title":"Structure Property Relationships of Carboxylic Acid Isosteres","volume":"59","author":"Lassalas","year":"2016","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0535","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1021\/cr950066q","article-title":"Bioisosterism: A Rational Approach in Drug Design","volume":"96","author":"Patani","year":"1996","journal-title":"Chem Rev"},{"key":"10.1016\/j.drudis.2022.07.007_b0540","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10847-013-0334-x","article-title":"Tetrazoles as carboxylic acid isosteres: chemistry and biology","volume":"78","author":"Malik","year":"2013","journal-title":"J Incl Phenom Macrocycl Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0545","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1039\/c0md00263a","article-title":"Synthesis and biological evaluation of tetrazole containing compounds as possible anticancer agents","volume":"2","author":"Kumar","year":"2011","journal-title":"MedChemComm"},{"key":"10.1016\/j.drudis.2022.07.007_b0550","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bmcl.2018.11.005","article-title":"Synthesis, biological evaluation and molecular dynamic simulations of novel Benzofuran-tetrazole derivatives as potential agents against Alzheimer's disease","volume":"29","author":"Kushwaha","year":"2019","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.drudis.2022.07.007_b0555","doi-asserted-by":"crossref","first-page":"8967","DOI":"10.1021\/acs.jmedchem.6b00908","article-title":"Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer\u2019s Disease","volume":"59","author":"Rabal","year":"2016","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0560","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/npp.2016.163","article-title":"A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice","volume":"42","author":"Cuadrado-Tejedor","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"10.1016\/j.drudis.2022.07.007_b0565","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1021\/acschemneuro.0c00448","article-title":"Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents","volume":"11","author":"Patel","year":"2020","journal-title":"ACS Chem Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0570","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1021\/acschemneuro.9b00226","article-title":"Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents","volume":"10","author":"Patel","year":"2019","journal-title":"ACS Chem Neurosci"},{"key":"10.1016\/j.drudis.2022.07.007_b0575","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1021\/ci400518g","article-title":"Accurately Predicting CYP-Mediated Sites of Metabolism with Neural Networks","volume":"53","author":"Zaretzki","year":"2013","journal-title":"J Chem Inf Model"},{"key":"10.1016\/j.drudis.2022.07.007_b0580","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1021\/acs.jmedchem.1c00048","article-title":"Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer\u2019s Disease","volume":"64","author":"Rossi","year":"2021","journal-title":"J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0585","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.2174\/1568026617666170717114944","article-title":"Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core","volume":"17","author":"Lin","year":"2017","journal-title":"Curr Top Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0590","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.ejmech.2016.10.060","article-title":"A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer's disease","volume":"128","author":"Sameem","year":"2017","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.drudis.2022.07.007_b0595","doi-asserted-by":"crossref","first-page":"108552","DOI":"10.1016\/j.jnutbio.2020.108552","article-title":"Signaling mechanisms underlying inhibition of neuroinflammation by resveratrol in neurodegenerative diseases","volume":"88","author":"Huang","year":"2021","journal-title":"J Nutr Biochem"}],"container-title":["Drug Discovery Today"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1359644622002926?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1359644622002926?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T13:00:46Z","timestamp":1761224446000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1359644622002926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":119,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["S1359644622002926"],"URL":"https:\/\/doi.org\/10.1016\/j.drudis.2022.07.007","relation":{},"ISSN":["1359-6446"],"issn-type":[{"value":"1359-6446","type":"print"}],"subject":[],"published":{"date-parts":[[2022,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Pivotal role of nitrogen heterocycles in Alzheimer\u2019s disease drug discovery","name":"articletitle","label":"Article Title"},{"value":"Drug Discovery Today","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.drudis.2022.07.007","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"103322"}}