For 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 h MAO. 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 h MAO-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. • Synthesized fluoxetine and sertraline based concomitant inhibitors ChEs and MAO for the treatment of AD. • Most of the compounds displayed activity in the range of submicromolar to nanomolar range. • Five compounds possessed excellent simultaneous inhibitory activity against all the four tested targets. • In-vivo cytotoxicity and Ex-vivo experiment on Swiss albino mice also performed. • Docking Studies carried out to confirm the in-vitro data. [ABSTRACT FROM AUTHOR]