期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 84, 期 -, 页码 107-117出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.07.021
关键词
Tetrahydrobenzo[h][1,6]naphthyridines; Multitarget compounds; Dual binding site AChE inhibitors; A beta aggregation inhibitors; Tau aggregation inhibitors
资金
- Ministerio de Ciencia e Innovacion (MICINN) [CTQ2011-22433, CTQ2012-30930, SAF2011-27642, SAF2009-10553]
- Ramon y Cajal program
- Generalitat de Catalunya (GC) [2009SGR1396, 2009SGR1024, 2009SGR249]
- Xarxa de Recerca en Quimica Tearica i Computacional (XRQTC)
- Ramon y Cajal program of MICINN
- Juan de la Cierva program of Ministerio de Economia y Competitividad
- ICREA
Optimization 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 -6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-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-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent A beta 42 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-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. (c) 2014 Elsevier Masson SAS. All rights reserved.
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