Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease

详细信息    查看全文

• 作者：Oscar M. Bautista-Aguilera^a ; ¹ ; Gerard Esteban^b ; ¹ ; Irene Bolea^b ; Katarina Nikolic^c ; Danica Agbaba^c ; Ignacio Moraleda^d ; Isabel Iriepa^d ; Abdelouahid Samadi^a ; Elena Soriano^e ; Mercedes Unzeta^b ; José ; Marco-Contelles^a ; ^{iqoc21@iqog.csic.es" class="auth_mail}
• 关键词：Donepezil ; Donepezil&ndash ; indolyl hybrids ; EeAChE ; eqBuChE ; hMAO A ; hMAO B ; Inhibitors ; 3D-QSAR ; Molecular modeling ; ADMET
• 刊名：European Journal of Medicinal Chemistry
• 出版年：21 March, 2014
• 年：2014
• 卷：75
• 期：Complete
• 页码：82-95
• 全文大小：1695 K

文摘

The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 m>versusm> 7 and 8) or equipotent (see compounds 14, 15 m>versusm> 9 and 10) than the corresponding amides, showing a clear m>Eem>AChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as m>Eem>ACE and MAO A inhibitors. Propargylamine 15 [m>Nm>-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1m>Hm>-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC₅₀聽=聽5.5聽卤聽1.4聽nM) and moderately potent hMAO B (IC₅₀聽=聽150聽卤聽31聽nM), m>Eem>AChE (IC₅₀聽=聽190聽卤聽10聽nM), and eqBuChE (IC₅₀聽=聽830聽卤聽160聽nM) inhibitor. However, the analogous m>Nm>-allyl and the m>Nm>-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.