Fluoxetine and sertraline based multitarget inhibitors of cholinesterases and monoamine oxidase-A/B for the treatment of Alzheimer's disease: Synthesis, pharmacology and molecular modeling studies

Int J Biol Macromol. 2021 Oct 20;193(Pt A):19-26. doi: 10.1016/j.ijbiomac.2021.10.102. Online ahead of print.ABSTRACTFor the potential therapy of Alzheimer's disease (AD), cholinesterases (ChE) and monoamine oxidase (MAO) are key enzymes that regulate the level of acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) and monoamines. The aim of current research is the synthesis of multi-target compounds that can concomitantly inhibit ChEs and MAO. A series of fluoxetine and sertraline hybrids was designed and evaluated as multi-target inhibitors of ChEs and hMAO. In-vitro enzyme inhibition studies demonstrated that a number of compounds displayed excellent inhibition in submicromolar to nanomolar range. However, compounds 17, 22, 38-40 possess excellent concomitant inhibitory activity against ChEs and hMAO-A/B enzymes and thus emerged as optimal multi-target hybrids. In-vivo acute toxicity study showed the safety of synthesized compounds up to 2000 mg/kg dose. The examinations of brain tissue in Swiss albino mice suggested that selected most active MAO-B inhibitors 17 and 22 have a propensity to block the MAO-B activity that could be responsible for their neurodegenerative effect in mice. The in-vitro inhibitory manner of interaction of these multipotent compounds on all four targets were confirmed by molecular docking investigations.PMID:34687762 | DOI:10.1016/j.ijbiomac.2021.10.102
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Source Type: research