{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T04:31:05Z","timestamp":1783744265242,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["20-19638Y"],"award-info":[{"award-number":["20-19638Y"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"ERDF","doi-asserted-by":"publisher","award":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000841"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000841"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["SVV 260 547"],"award-info":[{"award-number":["SVV 260 547"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>2,5-Disubstituted 1,3,4-oxadiazoles are privileged versatile scaffolds in medicinal chemistry that have exhibited diverse biological activities. Acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors are used, e.g., to treat dementias and myasthenia gravis. 5-Aryl-1,3,4-oxadiazoles decorated with dodecyl linked via nitrogen, sulfur or directly to this heterocycle have been designed as potential inhibitors of AChE and BChE. They were prepared from commercially available or in-house prepared hydrazides by reaction with dodecyl isocyanate to form hydrazine-1-carboxamides 2 (yields 67\u201398%) followed by cyclization using p-toluenesulfonyl chloride and triethylamine in 41\u2013100% yields. Thiadiazole isostere was also synthesized. The derivatives were screened for inhibition of AChE and BChE using Ellman\u2019s spectrophotometric method. The compounds showed a moderate dual inhibition with IC50 values of 12.8\u201399.2 for AChE and from 53.1 \u00b5M for BChE. All the heterocycles were more efficient inhibitors of AChE. The most potent inhibitor, N-dodecyl-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine 3t, was subjected to advanced reversibility and type of inhibition evaluation. Structure\u2013activity relationships were identified. Many oxadiazoles showed lower IC50 values against AChE than established drug rivastigmine. According to molecular docking, the compounds interact non-covalently with AChE and BChE and block entry into enzyme gorge and catalytic site, respectively.<\/jats:p>","DOI":"10.3390\/ph15040400","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:29:36Z","timestamp":1648416576000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["5-Aryl-1,3,4-oxadiazol-2-amines Decorated with Long Alkyl and Their Analogues: Synthesis, Acetyl- and Butyrylcholinesterase Inhibition and Docking Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-9334","authenticated-orcid":false,"given":"V\u00e1clav","family":"Pfl\u00e9gr","sequence":"first","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, Akademika Heyrovsk\u00e9ho 1203, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-5258","authenticated-orcid":false,"given":"\u0160\u00e1rka","family":"\u0160t\u011bp\u00e1nkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentsk\u00e1 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6961-6151","authenticated-orcid":false,"given":"Katar\u00edna","family":"Svr\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentsk\u00e1 573, 532 10 Pardubice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark\u00e9ta","family":"\u0160varcov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, Akademika Heyrovsk\u00e9ho 1203, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"},{"name":"Department of Chemistry, Faculty of Science, J. E. Purkinje University, Pasteurova 3632\/15, 400 96 \u00dast\u00ed nad Labem, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarmila","family":"Vin\u0161ov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, Akademika Heyrovsk\u00e9ho 1203, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4600-8409","authenticated-orcid":false,"given":"Martin","family":"Kr\u00e1tk\u00fd","sequence":"additional","affiliation":[{"name":"Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, Akademika Heyrovsk\u00e9ho 1203, 500 05 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.31482\/mmsl.2013.015","article-title":"Modeling the binding of CWAs to human AChE and BuChE","volume":"8","author":"Bennion","year":"2013","journal-title":"Mil. Med. Sci. Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0378-4274(95)03575-3","article-title":"Structural bases for the specificity of cholinesterase catalysis and inhibition","volume":"82","author":"Taylor","year":"1995","journal-title":"Toxicol. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2174\/1570159X11311030006","article-title":"Acetylcholinesterase Inhibitors: Pharmacology and Toxicology","volume":"11","year":"2013","journal-title":"Curr. Neuropharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1042\/bj0262056","article-title":"Choline-esterase. An enzyme present in the blood-serum of the horse","volume":"26","author":"Stedman","year":"1932","journal-title":"Biochem. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrn1035","article-title":"Neurobiology of butyrylcholinesterase","volume":"4","author":"Darvesh","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1017\/S1461145705005833","article-title":"Targeting acetylcholinesterase and butyrylcholinesterase in dementia","volume":"9","author":"Lane","year":"2006","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.5507\/bp.2011.036","article-title":"Cholinesterases, a target of pharmacology and toxicology","volume":"155","author":"Pohanka","year":"2011","journal-title":"Biomed. Pap."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0079-6123(08)62380-8","article-title":"Cholinergic systems: Human diseases, animal models, and prospects for therapy","volume":"98","author":"Price","year":"1993","journal-title":"Prog. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/1531-8249(200002)47:2<162::AID-ANA5>3.0.CO;2-Q","article-title":"The spectrum of mutations causing end-plate acetylcholinesterase deficiency","volume":"47","author":"Ohno","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1097\/00019052-199910000-00008","article-title":"Immunology of the neuromuscular junction and presynaptic nerve terminal","volume":"12","author":"Vincent","year":"1999","journal-title":"Curr. Opin. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.abb.2009.12.005","article-title":"Butyrylcholinesterase for protection from organophosphorus poisons: Catalytic complexities and hysteretic behavior","volume":"494","author":"Masson","year":"2010","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1016\/0041-0101(94)90416-2","article-title":"Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger-RNA","volume":"32","author":"Jbilo","year":"1994","journal-title":"Toxicon"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107355","DOI":"10.1016\/j.compbiolchem.2020.107355","article-title":"In silico modeling for dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes in Alzheimer\u2019s disease","volume":"88","author":"Kumar","year":"2020","journal-title":"Comput. Biol. Chem."},{"key":"ref_14","first-page":"253","article-title":"Review: Oxadiazole Their Chemistry and Pharmacological Potentials","volume":"2","author":"Sharma","year":"2010","journal-title":"Pharma Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1080\/00397911.2013.879901","article-title":"Review of synthesis of 1,3,4-oxadiazole derivatives","volume":"44","author":"Patel","year":"2014","journal-title":"Synth. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1021\/jm2013248","article-title":"Oxadiazoles in medicinal chemistry","volume":"55","author":"Hogner","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s42250-019-00084-9","article-title":"A Review on the Preparation of 1,3,4-Oxadiazoles from the Dehydration of Hydrazines and Study of Their Biological Roles","volume":"2","author":"Nayak","year":"2019","journal-title":"Chem. Afr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"789","DOI":"10.2174\/138955712801264800","article-title":"1,3,4-Oxadiazole: A biologically active scaffold","volume":"12","author":"Khalilullah","year":"2012","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.2174\/1389557518666180524112050","article-title":"1,2,4-Oxadiazole as a Privileged Scaffold for Anti-inflammatory and Analgesic Activities: A Review","volume":"18","author":"Chawla","year":"2018","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2174\/1389557518666181015152433","article-title":"A Review Exploring Therapeutic Worth of 1,3,4-Oxadiazole Tailored Compounds","volume":"19","author":"Verma","year":"2019","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.ejmech.2018.04.017","article-title":"New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action","volume":"151","author":"Madacki","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17377","DOI":"10.1021\/ja055438j","article-title":"Elucidation of Fatty Acid Amide Hydrolase Inhibition by Potent \u03b1-Ketoheterocycle Derivatives from Monte Carlo Simulations","volume":"127","author":"Guimaraes","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30781","DOI":"10.1039\/D1RA03718H","article-title":"The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer\u2019s agents: Highlights from 2010 to 2020","volume":"11","author":"Kareem","year":"2021","journal-title":"RSC Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111707","DOI":"10.1016\/j.ejmech.2019.111707","article-title":"Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer\u2019s disease","volume":"183","author":"Tripathi","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103025","DOI":"10.1016\/j.bioorg.2019.103025","article-title":"Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions","volume":"89","author":"Mishra","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1515\/hc-2018-0166","article-title":"Synthesis and bioactivity of novel C2-glycosyl oxadiazole derivatives as acetylcholinesterase inhibitors","volume":"24","author":"Wang","year":"2018","journal-title":"Heterocycl. Comm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1007\/s00706-019-02462-y","article-title":"Synthesis of indole-2-carbohydrazides and 2-(indol-2-yl)-1,3,4-oxadiazoles as antioxidants and their acetylcholinesterase inhibition properties","volume":"150","author":"Bingul","year":"2019","journal-title":"Monatsh. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kr\u00e1tk\u00fd, M., Baranyai, Z., \u0160t\u011bp\u00e1nkov\u00e1, \u0160., Svr\u010dkov\u00e1, K., \u0160varcov\u00e1, M., Stola\u0159\u00edkov\u00e1, J., Horv\u00e1th, L., B\u0151sze, S., and Vin\u0161ov\u00e1, J. (2020). N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity. Molecules, 25.","DOI":"10.3390\/molecules25102268"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.2174\/1568026620666200819155503","article-title":"Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors","volume":"20","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13065-018-0497-z","article-title":"Molecular docking studies of coumarin hybrids as potential acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A\/B and \u03b2-amyloid inhibitors for Alzheimer\u2019s disease","volume":"12","author":"Yusufzai","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1081\/NCN-100105903","article-title":"Synthesis and structure determination of some oxadiazole-2-thione and triazole-3-thione galactosides","volume":"20","author":"Ahmad","year":"2001","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ujan, R., Saeed, A., Channar, P.A., Larik, F.A., Abbas, Q., Alajmi, M.F., El-Seedi, H.R., Rind, M.A., Hassan, M., and Raza, H. (2019). Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation. Molecules, 24.","DOI":"10.3390\/molecules24050860"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.chroma.2006.11.029","article-title":"Characterization of reversible and pseudo-irreversible acetylcholinesterase inhibitors by means of an immobilized enzyme reactor","volume":"1144","author":"Bartolini","year":"2007","journal-title":"J. Chromatogr. A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1021\/ja01318a036","article-title":"The determination of enzyme dissociation constants","volume":"56","author":"Lineweaver","year":"1934","journal-title":"J. Am. Chem. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1021\/acs.jmedchem.5b00608","article-title":"Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis","volume":"59","author":"Karabanovich","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10337","DOI":"10.1021\/jo401751h","article-title":"I2-Mediated Oxidative C\u2013O Bond Formation for the Synthesis of 1,3,4-Oxadiazoles from Aldehydes and Hydrazides","volume":"78","author":"Yu","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1016\/j.ejmech.2009.05.009","article-title":"Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid","volume":"44","author":"Hearn","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","first-page":"293","article-title":"Half-inhibition concentrations of new cholinesterase inhibitors","volume":"59","author":"Zdrazilova","year":"2004","journal-title":"Z. Nat. C"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ab.2007.07.023","article-title":"Limitation of the Ellman method: Cholinesterase activity measurement in the presence of oximes","volume":"370","author":"Sinko","year":"2007","journal-title":"Anal. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Autodock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/4\/400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:43:16Z","timestamp":1760136196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/4\/400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ph15040400"],"URL":"https:\/\/doi.org\/10.3390\/ph15040400","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}