Two series of fluorinated chalcones containing morpholine and imidazole-based compounds (f1-f8) were synthesized and evaluated for recombinant human monoamine oxidase (MAO)-A and -B as well as acetylcholinesterase inhibitory activities.Our results indicate that morpholine containing chalcones are highly selective MAO-B inhibitors having reversibility properties. All the imidazole-based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds, (2E)-3-(3-fluorophenyl)-1- [4-(morpholin-4-yl)phenyl]prop-2-en-1-one (f2) showed potent inhibitory activity for recombinant human MAO-B (IC 50 = 0.087 μM) with a high selectivity index (SI) of 517.2. In the recovery experiments using dialysis, the residual activity of MAO-B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the K i values of f1 and f2 for MAO-B were 0.027 and 0.020 μM, respectively, with competitive patterns. All the morpholine-based compounds (f1-f4) showed moderate inhibition toward acetylcholinesterase with IC 50 values ranging between 24 and 54 μM. All morpholine-containing compounds exhibit good blood-brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO-B inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies. K E Y W O R D S acetylcholinesterase, chalcone, entrance cavity, imidazole, MAO-B selective inhibitor, molecular dynamics, morpholine Parkinson's disease (PD) encompasses a multicentric progressive loss of specific neuronal cell populations resulting in the development of the movement disorder. PD is the second most prevalent age-related neurodegenerative disease that results from the loss of nigrostriatal dopaminergic neurons. [1] The neurodegeneration is initiated decades before it affects the motor function, and the phenotype is usually characterized by resting tremors, rigidity, and bradykinesia. [2] Monoamine oxidase (MAO; EC 1.4.3.4) has increased expression levels in neuronal tissues as well as gastro and hepatic tissues. [3] MAO-A and MAO-B inhibitors are in clinical use for the treatment of neurological and psychiatric disorders, respectively. [4] Biochemically, these two isoenzymes are differentiated by their substrate and inhibitor specificities. [5] Inhibition of isoform B, which is mainly localized in the raphe nucleus of serotonergic neuronal cell bodies, leads to elevated levels of dopamine (DA) in Parkinsonism patients. The phenomenal advances in neurochemistry have greatly helped in unfolding the pathophysiology of this disorder and provided the basis for the introduction of levodopa. The new understanding and disclosure of the mechanisms of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in primate models has triggered a resurgence concerning the etiological factors that enhance the inhibition of MAO-B with deprenyl, the first MAO-B inhibitor which potentiates the effects of levodopa and prolongs the life of PD patients. [6]Most MAO-B inh...