ae7b4b0838875cf634e15db59c2d66a2 molecules_a2018v23n3p634.pdf 84812c87d327b8fa12821893653c83d9eafc838f molecules_a2018v23n3p634.pdf 2f60ab1c778f9676beb18880fe1aa67615a7595ae2bcfa1ba1a0ed243ead847f molecules_a2018v23n3p634.pdf Syntax Error: Couldn't find trailer dictionary Syntax Error: Invalid XRef entry Syntax Error: Top-level pages object is wrong type (null) Syntax Error: Top-level pages object is wrong type (null) Syntax Error: Top-level pages object is wrong type (null) Syntax Error: Top-level pages object is wrong type (null) Title: Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis Subject: Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis. Keywords: acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; quinolinium compounds; triazoles; structural biology; copper-catalyzed azide-alkyne cycloaddition; click chemistry Author: Carles Galdeano, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Manuela Bartolini, Belén Pérez, M. Victòria Clos, Israel Silman, Ludovic Jean, Jacques-Philippe Colletier, Pierre-Yves Renard and Diego Muñoz-Torrero Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.17; modified using iText® 7.0.1 ©2000-2016 iText Group NV (AGPL-version) CreationDate: Wed Mar 14 02:36:55 2018 CET ModDate: Wed Mar 14 04:00:32 2018 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 19 Encrypted: no Page size: 0 x 0 pts Page rot: 0 File size: 4047907 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OXBKYU+TeXGyreAdventor-Bold Type 1 Custom yes yes no 93 0 WEQVKZ+VnURWPalladioL-Bold Type 1 Custom yes yes no 94 0 GZMBIM+VnURWPalladioL Type 1 Custom yes yes no 96 0 GPASDR+URWPalladioL-Ital Type 1 Custom yes yes no 91 0 NBNBYH+URWPalladioL-Bold Type 1 Custom yes yes no 92 0 ZAHUAK+URWPalladioL-Roma Type 1 Custom yes yes no 95 0 PUSVWS+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 101 0 CIDFont+F2 CID TrueType Identity-H yes no yes 145 0 CIDFont+F3 CID TrueType Identity-H yes no yes 146 0 CIDFont+F1 CID TrueType Identity-H yes no yes 147 0 CIDFont+F4 CID TrueType Identity-H yes no yes 148 0 RGUFCP+CMSY10 Type 1 Builtin yes yes no 259 0 CIDFont+F2 CID TrueType Identity-H yes no yes 261 0 CIDFont+F3 CID TrueType Identity-H yes no yes 262 0 CIDFont+F1 CID TrueType Identity-H yes no yes 263 0 CIDFont+F4 CID TrueType Identity-H yes no yes 264 0 CIDFont+F2 CID TrueType Identity-H yes no yes 398 0 CIDFont+F3 CID TrueType Identity-H yes no yes 399 0 CIDFont+F1 CID TrueType Identity-H yes no yes 400 0 CIDFont+F4 CID TrueType Identity-H yes no yes 401 0 XIRVNA+EURB10 Type 1 Builtin yes yes no 552 0 OHREHB+URWPalladioL-BoldItal Type 1 Custom yes yes no 553 0 HYYHEA+CMBSY10 Type 1 Builtin yes yes no 554 0 VPGGRR+EURM10 Type 1 Builtin yes yes no 555 0 CIDFont+F2 CID TrueType Identity-H yes no yes 597 0 CIDFont+F3 CID TrueType Identity-H yes no yes 598 0 CIDFont+F1 CID TrueType Identity-H yes no yes 599 0 CIDFont+F4 CID TrueType Identity-H yes no yes 600 0 JILQEY+PazoMath-Italic Type 1 Builtin yes yes no 642 0 CIDFont+F2 CID TrueType Identity-H yes no yes 644 0 CIDFont+F3 CID TrueType Identity-H yes no yes 645 0 CIDFont+F1 CID TrueType Identity-H yes no yes 646 0 CIDFont+F4 CID TrueType Identity-H yes no yes 647 0 CIDFont+F6 CID TrueType Identity-H yes no yes 648 0 CIDFont+F2 CID TrueType Identity-H yes no yes 695 0 CIDFont+F3 CID TrueType Identity-H yes no yes 696 0 CIDFont+F1 CID TrueType Identity-H yes no yes 697 0 CIDFont+F4 CID TrueType Identity-H yes no yes 698 0 CIDFont+F6 CID TrueType Identity-H yes no yes 699 0 Jhove (Rel. 1.6, 2011-01-04) Date: 2019-02-14 17:32:42 CET RepresentationInformation: molecules_a2018v23n3p634.pdf ReportingModule: BYTESTREAM, Rel. 1.3 (2007-04-10) LastModified: 2019-01-29 11:00:08 CET Size: 4047907 Format: bytestream Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/octet-stream Checksum: 106c30bc Type: CRC32 Checksum: ae7b4b0838875cf634e15db59c2d66a2 Type: MD5 Checksum: 84812c87d327b8fa12821893653c83d9eafc838f Type: SHA-1