Di Pietro, O.Pérez Areales, Francisco JavierJuárez-Jiménez, JordiEspargaró Colomé, AlbaClos, VictòriaPérez Fernández, BelénLavilla Grífols, RodolfoSabaté Lagunas, RaimonLuque Garriga, F. XavierMuñoz-Torrero López-Ibarra, Diego2014-10-292014-10-292014-09-120223-5234https://hdl.handle.net/2445/59194Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine<br>6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b<br>d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a<br>d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a<br>d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.11 p.application/pdfeng(c) Elsevier Masson SAS, 2014Disseny de medicamentsInhibidors enzimàticsMalaltia d'AlzheimerPèptidsProteïnesDrug designEnzyme inhibitorsAlzheimer's diseasePeptidesProteinsinfo:eu-repo/semantics/article6424992014-10-29info:eu-repo/semantics/openAccess