Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine

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• 作者：Abdelouahid Samadi^a ; ^{samadi@iqog.csic.es} ; Cristó ; bal de los Rí ; os^b ; ^c ; ^{cristobal.delosrios@uam.es} ; Irene Bolea^d ; ^{irene_bolea@hotmail.com} ; Mourad Chioua^a ; ^{mchioua@iqog.csic.es} ; Isabel Iriepa^b ; ^{isabel.iriepa@uah.es} ; Ignacio Moraleda^b ; ^{ignacio.moraleda@uah.es} ; Manuela Bartolini^e ; ^{manuela.bartolini3@unibo.it} ; Vincenza Andrisano^e ; ^{vincenza.andrisano@unibo.it} ; Enrique Gá ; lvez^b ; ^{enrique.galvez@uah.es} ; Carolina Valderas^a ; ^{carolina.valderas@iqog.csic.es} ; Mercedes Unzeta^d ; ^{mercedes.unzeta@uab.cat} ; José ; Marco-Contelles^a ; ^{jlmarco@iqog.csic.es}
• 关键词：Indoles ; Naphthyridines ; Multipotent molecules ; EeAChE ; eqBuChE ; MAO-A ; MAO-B ; Kinetic analysis ; Inhibition mechanism ; Molecular modeling ; Amyloid ¦Â ; Alzheimer's disease
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June, 2012
• 年：2012
• 卷：52
• 期：Complete
• 页码：251-262
• 全文大小：1076 K

文摘

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?¡À?2?nM) and a moderately selective eqBuChE inhibitor (IC₅₀?=?4.7?¡À?0.2?¦ÌM). 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?¡À?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¦Â aggregation induced by hAChE by 30.6 % .