期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 -, 页码 251-262出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.03.022
关键词
Indoles; Naphthyridines; Multipotent molecules; EeAChE; eqBuChE; MAO-A; MAO-B; Kinetic analysis; Inhibition mechanism; Molecular modeling; Amyloid beta; Alzheimer's disease
资金
- CSIC
- ISCIII (MICINN)
- MICINN [SAF2006-08764-C02-01, SAF2009-07271]
- CAM [S/SAL-0275-2006]
- ISCIII [CP10/00531]
- Fundacion CIEN
- Miguel Servet Program
- EU [CM1103]
The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC50 = 31 +/- 2 nM) and a moderately selective eqBuChE inhibitor (IC50 = 4.7 +/- 0.2 mu M). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC50 = 25 +/- 3 nM, K-i = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit A beta aggregation induced by hAChE by 30.6%. (C) 2012 Elsevier Masson SAS. All rights reserved.
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