{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T05:34:13Z","timestamp":1772775253792,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,11]],"date-time":"2022-12-11T00:00:00Z","timestamp":1670716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["18-13-00361"],"award-info":[{"award-number":["18-13-00361"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki\u2013Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A3-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53\u201396%). The bioactivity of all new compounds was evaluated by Ellman\u2019s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC50 of 0.25, 0.552, 0.089, 0.746, and 0.121 \u03bcM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.<\/jats:p>","DOI":"10.3390\/molecules27248787","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T05:10:19Z","timestamp":1670821819000},"page":"8787","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Design, Synthesis and Assay of Novel Methylxanthine\u2013Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Danila V.","family":"Reshetnikov","sequence":"first","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor D.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"The Federal Research Center Institute of Molecular Biology and Biophysics, Timakov Str., 2\/12, 630117 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1795-9256","authenticated-orcid":false,"given":"Dmitry S.","family":"Baev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-5271","authenticated-orcid":false,"given":"Tatyana V.","family":"Rybalova","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-9499","authenticated-orcid":false,"given":"Evgenii S.","family":"Mozhaitsev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4932-0091","authenticated-orcid":false,"given":"Sergey S.","family":"Patrushev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, Pirogova Str., 1, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin A.","family":"Vavilin","sequence":"additional","affiliation":[{"name":"The Federal Research Center Institute of Molecular Biology and Biophysics, Timakov Str., 2\/12, 630117 Novosibirsk, Russia"},{"name":"Novosibirsk State University, Pirogova Str., 1, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana G.","family":"Tolstikova","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"},{"name":"Novosibirsk State University, Pirogova Str., 1, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0761-9696","authenticated-orcid":false,"given":"Elvira E.","family":"Shults","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7156","DOI":"10.1021\/acs.jmedchem.1c00261","article-title":"The medicinal chemistry of caffeine","volume":"64","author":"Faudone","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Janitschke, D., Lauer, A.A., Bachmann, C.M., Grimm, H.S., Hartmann, T., and Grimm, M.O.W. (2021). Methylxanthines and neurodegenerative diseases: An update. Nutrients, 13.","DOI":"10.3390\/nu13030803"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s00018-007-7051-9","article-title":"Caffeine analogs: Biomedical impact","volume":"64","author":"Daly","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Monteiro, J.P., Alves, M.G., Oliveira, P.F., and Silva, B.M. (2016). Structure-bioactivity relationships of methylxanthines: Trying to make sense of all the promises and the drawbacks. Molecules, 21.","DOI":"10.3390\/molecules21080974"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00829","DOI":"10.1016\/j.heliyon.2018.e00829","article-title":"Xanthine scaffold: Scope and potential in drug development","volume":"4","author":"Singh","year":"2018","journal-title":"Heliyon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.bbrc.2021.07.051","article-title":"Neuroprotective effects of theobromine in transient global cerebral ischemia-reperfusion rat model","volume":"571","author":"Bhat","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000139480","article-title":"Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor\/Ca2+ release channel","volume":"54","author":"Liu","year":"1997","journal-title":"Pharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Schepici, G., Silvestro, S., Bramanti, P., and Mazzon, E. (2020). Caffeine: An over-view of its beneficial effects in experimental models and clinical trials of Parkinson\u2019s disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134766"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1600670","DOI":"10.1002\/mnfr.201600670","article-title":"Health benefits of methylxanthines in neurodegenerative diseases","volume":"61","author":"Franco","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0378-4274(91)90015-X","article-title":"Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives","volume":"55","author":"Karadsheh","year":"1991","journal-title":"Toxicol. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1039\/c2fo10174b","article-title":"Inhibition of acetylcholinesterase by green and white tea and their simulated intestinal metabolites","volume":"3","author":"Okello","year":"2012","journal-title":"Food Funct."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9873","DOI":"10.3390\/ijms14059873","article-title":"Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase","volume":"14","author":"Pohanka","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"543","DOI":"10.2174\/1389557514666140529223436","article-title":"The effects of caffeine on the cholinergic system","volume":"14","author":"Pohanka","year":"2014","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.2174\/1389557522666220413103529","article-title":"Role of Caffeine in the Age-related Neurodegenerative Diseases: A Review","volume":"22","author":"Pohanka","year":"2022","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.neuropharm.2018.03.041","article-title":"A novel pharmacological activity of caffeine in the cholinergic system","volume":"135","author":"Fabiani","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yelanchezian, Y.M.M., Waldfogel, H.J., Faull, R.L.M., and Kwakowsky, A. (2022). Neuroprotective effect of caffeine in Alzheimer\u2019s disease. Molecules, 27.","DOI":"10.3390\/molecules27123737"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.2174\/0929867329666220218094501","article-title":"A2A Adenosine receptor antagonists and their potential in neurological disorders","volume":"29","author":"Lambertucci","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_18","first-page":"137","article-title":"Medicinal chemistry of A2B adenosine receptors","volume":"Volume 34","author":"Borea","year":"2018","journal-title":"The Adenosine Receptors"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1055\/s-2002-28517","article-title":"1-Benzyl-4-chloromethylpiperidine: A Building block in the synthesis of compounds of pharmacological interest","volume":"2002","year":"2002","journal-title":"Synthesis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6795","DOI":"10.1016\/j.bmc.2005.07.019","article-title":"Design and synthesis of N- benzylpiperidine-purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase","volume":"13","author":"Perez","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.1016\/j.bmcl.2013.05.092","article-title":"Selective inhibition of human acetylcholinesterase by xanthine derivatives: In vitro inhibition and molecular modeling investigations","volume":"23","author":"Mohamed","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1124\/molpharm.121.000415","article-title":"New synthetic caffeine analogs as modulators of the cholinergic system","volume":"101","author":"Fabiani","year":"2022","journal-title":"Mol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s00702-012-0948-y","article-title":"Propargylamine-derived multitarget-directed ligands: Fighting Alzheimer\u2019s disease with monoamine oxidase inhibitors","volume":"120","author":"Bolea","year":"2013","journal-title":"J. Neural Transm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10455","DOI":"10.1021\/jm501501a","article-title":"N-Methyl-N-((1-methyl-5-(3-(1-(2-methyl benzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor","volume":"57","author":"Samadi","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4155\/fmc.15.12","article-title":"Propargylamine as functional moiety in the design of multifunctional drugs for neurodegenerative disorders: MAO inhibition and beyond","volume":"7","author":"Zindo","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/acs.jmedchem.8b00760","article-title":"Polypharmacology by design: A medicinal chemist\u2019s perspective on multitargeting compounds","volume":"62","author":"Proschak","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4835","DOI":"10.1016\/j.bmc.2016.06.045","article-title":"Design, synthesis and biological evaluation of N-methyl-N-[(1,2,3-triazol-4- yl)alkyl]propargylamines as novel monoamine oxidase B inhibitors","volume":"24","author":"Alencar","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ramsay, R.R., and Tipton, K.F. (2017). Assessment of enzyme inhibition: A review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs. Molecules, 22.","DOI":"10.20944\/preprints201707.0019.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.ejmech.2019.05.039","article-title":"Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase","volume":"177","author":"Kumar","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111572","DOI":"10.1016\/j.ejmech.2019.111572","article-title":"The chemistry toolbox of multitarget-directed ligands for Alzheimer\u2019s disease","volume":"181","author":"Mesiti","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"126880","DOI":"10.1016\/j.bmcl.2019.126880","article-title":"Propargylamine-derived multi-target directed ligands for Alzheimer\u2019s disease therapy","volume":"30","author":"Carreiras","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105301","DOI":"10.1016\/j.bioorg.2021.105301","article-title":"Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study","volume":"116","author":"Vu","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1021\/acschemneuro.2c00132","article-title":"Design, synthesis, and pharmacological evaluation of N-propargylated diphenylpyrimidines as multitarget directed ligands for the treatment of Alzheimer\u2019s disease","volume":"13","author":"Kumar","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8251","DOI":"10.1021\/jm200853t","article-title":"Synthesis, biological evaluation and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]- N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase\/monoamine oxidase inhibitors for the treatment of Alzheimer\u2019s disease","volume":"54","author":"Bolea","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ejmech.2013.12.028","article-title":"Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase\/monoamine oxidase inhibitors for the potential treatment of Alzheimer\u2019s disease","volume":"75","author":"Esteban","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.ejmech.2014.04.078","article-title":"Donepezil+propargylamine+8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer\u2019s disease","volume":"80","author":"Wang","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_37","first-page":"294","article-title":"ASS234, as a new multi-target directed propargylamine for Alzheimer\u2019s disease therapy","volume":"10","author":"Unzeta","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Guieu, B., Lecoutey, C., Legay, R., Davis, A., Sopkova de Oliveira Santos, J., Altomare, C.D., Catto, M., Rochais, C., and Dallemagne, P. (2021). First synthesis of racemic trans propargylamino donepezil, a pleiotrope agent able to both inhibit AChE and MAOB, with potential interest against Alzheimer\u2019s disease. Molecules, 26.","DOI":"10.3390\/molecules26010080"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1055\/s-0031-129036","article-title":"8-Bromocaffeine (8-BC): A New versatile reagent for conversion of aldoximes into nitriles","volume":"23","author":"Rad","year":"2012","journal-title":"Synlett"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s10600-020-03169-x","article-title":"Synthetic transformations of sesquiterpene lactones. 11. Conjugates based on caffeine and eudesmanolides with N-containing linkers","volume":"56","author":"Reshetnikov","year":"2020","journal-title":"Chem. Nat. Compd."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"871","DOI":"10.3987\/COM-02-9463","article-title":"Synthesis of 8-Substituted Xanthine Derivatives by Suzuki Cross-Coupling Reaction","volume":"57","author":"Vollmann","year":"2002","journal-title":"Heterocycles"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/(SICI)1521-3773(20000103)39:1<165::AID-ANIE165>3.0.CO;2-B","article-title":"Phosphane-free palladium-catalyzed coupling reactions: The decisive role of Pd nanoparticles","volume":"39","author":"Reetz","year":"2000","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Albuquerque, H.M.T., Pinto, D.C.G.A., and Silva, A.M.S. (2021). Microwave irradiation: Alternative heating process for the synthesis of biologically applicable chromones, quinolones, and their precursors. Molecules, 26.","DOI":"10.3390\/molecules26206293"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1135\/cccc19872730","article-title":"7-Alkyl-8-ethinyltheophylline","volume":"52","author":"Pfleiderer","year":"1987","journal-title":"Collect. Czeh. Chem. Commun."},{"key":"ref_45","unstructured":"Thompson, R., Beauglehole, A., and Wang, G. (2016). Xanthine-Substituted Alkynyl Carbamates\/Reverse Carbamates as A2B Antagonists. (WO\/2016\/164838), Publication Number, International Application No. PCT\/US2016\/026807."},{"key":"ref_46","unstructured":"Arsenjans, P., Vasiljeva, J., Domracheva, I., Shestakova, I., Gulbe, A., Kanepe-Lapsa, I., Kauss, V., and Kalvins, I. (2016). Ethynylxanthines, preparation and use as calcium ion channel modulators. (WO 2016159747A), Publication Number, Application PCT\/LV2015\/000003 events."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s10593-020-02730-4","article-title":"8-Ethynylxanthines as promising antiproliferative agents, angiogenesis inhibitors, and calcium channel activity modulators","volume":"56","author":"Arsenjans","year":"2020","journal-title":"Chem. Heterocyclic Compd."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1039\/c2cs15356d","article-title":"A walk around the A3-coupling","volume":"41","author":"Peshkov","year":"2012","journal-title":"Chem. Soc. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14091","DOI":"10.1021\/acs.chemrev.7b00343","article-title":"Synthesis and Reactivity of Propargylamines in Organic Chemistry","volume":"117","author":"Lauder","year":"2017","journal-title":"Chem. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1039\/p298700000s1","article-title":"Tables of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond lengths in organic compounds","volume":"2","author":"Allen","year":"1987","journal-title":"J. Chem. Soc. Perkin Trans."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1107\/S0021889802022112","article-title":"Single-crystal structure validation with the program PLATON","volume":"36","author":"Spek","year":"2003","journal-title":"J. Appl. Cryst."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1016\/0024-3205(88)90478-X","article-title":"3,7-Dimethyl-1-propargylxanthine: A potent and selective in vivo antagonist of adenosine analogs","volume":"43","author":"Seale","year":"1988","journal-title":"Life Sci."},{"key":"ref_54","unstructured":"Sheldrick, G.M. (1996). SADABS, Program for Area Detector Adsorption Correction, Institute for Inorganic Chemistry, University of G\u00f6ttingen."},{"key":"ref_55","unstructured":"Sheldrick, G.M. (1997). SHELXS-97 and SHELXL-97\u2014Program for Crystal Structure Solution and Refinement, University of G\u00f6ttingen."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\u2014Integrated space-group and crystal-structure determination","volume":"A71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. A."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"C71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr. C"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13415","DOI":"10.1002\/chem.201102644","article-title":"Palladium-catalyzed desulfitative C-H arylation of heteroarenes with sodium sulfinates","volume":"17","author":"Liu","year":"2011","journal-title":"Chem. -A Eur. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1021\/jm00157a035","article-title":"Analogs of caffeine and theophylline: Effect of structural alterations on affinity at adenosine receptors","volume":"29","author":"Daly","year":"1986","journal-title":"J. Med. Chem."},{"key":"ref_60","unstructured":"(2016). Schrodinger Small Molecule Drug Discovery Suite, Schr\u00f6dinger, LLC."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"108698","DOI":"10.1016\/j.cbi.2019.06.011","article-title":"A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies","volume":"309","author":"Gerlits","year":"2019","journal-title":"Chem.-Biol. Interact."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2212Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_64","unstructured":"Biovia, D.S., Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., and Richmond, T.J. (2016). Dassault Syst\u00e8mes BIOVIA, Discovery Studio Visualizer, v.17.2, Dassault Syst\u00e8mes."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable Molecular Dynamics on CPU and GPU Architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/jcc.21816","article-title":"SwissParam: A Fast Force Field Generation Tool for Small Organic Molecules","volume":"32","author":"Zoete","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone \u03d5, \u03c8 and Side-Chain \u03c7 1 and \u03c7 2 Dihedral Angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. 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