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No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A 2A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A 2A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets. K E Y W O R D Sacetylcholinesterase, adenosine antagonist, monoamine oxidase, multitarget

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Objectives Considerable progress has been made in the treatment of Alzheimer's disease (AD), but all available strategies focus on alleviating symptoms rather than curing, which means that AD is viewed as an unresolvable neurodegenerative disease. Nanotechnological applications offer an alternative platform for the treatment of neurodegenerative diseases. This review aims to summarize the recent nanomedicine and nanotechnology developments for the treatment of AD. Key findings A plethora of nanocarriers and nanoparticle prodrugs have been reported to have negligible cytotoxicity in animal models, and these developments have revealed new opportunities for development of new classes of potent drug formulations for AD. Different nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes and metal-based carriers have been developed over the past decade, and they have been focusing on both neuroprotective and neurogenerative techniques to treat AD. Studies also reveal that nanotechnological approaches can aid in early diagnosis of AD and enhance therapeutic efficacy and bioavailability. Summary Notably, the drugs used conventionally to target the central nervous system have limitations that include an inability to cross the 'blood-brain barrier' or the 'blood-cerebrospinal fluid barrier' effectively and high drug efflux due to the activity of P-glycoprotein, but these limitations can be successfully overcome when nanocarriers are used for targeted drug delivery in AD.

a b s t r a c tDrug discovery and development are long and financially taxing processes. On an average it takes 12e15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC 50 values of 0.65 and 0.71 μM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 μM, although PC4 inhibited AChE by 56.6% (IC 50 = 8.77 μM). Compound PC3 effectively inhibited BACE-1 (IC 50 = 6.72 μM), and PC10 and PC11 moderately inhibited BACE-1 (IC 50 =14.9 and 15.3 μM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with K i values of 0.63 ± 0.13 and 0.53 ± 0.068 μM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.

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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...