Di Pietro_2014_Eur.J.Med.Chem_84C_107

Reference

Title : Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies - Di Pietro_2014_Eur.J.Med.Chem_84C_107
Author(s) : Di Pietro O , Perez-Areales FJ , Juarez-Jimenez J , Espargaro A , Clos MV , Perez B , Lavilla R , Sabate R , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 84C :107 , 2014
Abstract : 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 Abeta42 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.
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PubMedSearch : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedID: 25016233

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Citations formats

Di Pietro O, Perez-Areales FJ, Juarez-Jimenez J, Espargaro A, Clos MV, Perez B, Lavilla R, Sabate R, Luque FJ, Munoz-Torrero D (2014)
Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies
Eur Journal of Medicinal Chemistry 84C :107

Di Pietro O, Perez-Areales FJ, Juarez-Jimenez J, Espargaro A, Clos MV, Perez B, Lavilla R, Sabate R, Luque FJ, Munoz-Torrero D (2014)
Eur Journal of Medicinal Chemistry 84C :107