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Depression is identified as one of the most common psychiatric symptoms in Alzheimer's disease (AD). The comorbidity of AD and depression increases the burden of clinical treatment and care in elderly patients. In order to find new treatment options, we first proposed the dual RAGE/SERT inhibitors by fusing the key pharmacophore of vilazodone and azeliragon for the potential treatment of AD with comorbid depression. After a series of structural modifications, 34 dual-target directed ligands were designed and synthesized, and their RAGE and SERT inhibitory activities were systematically evaluated. Among them, compound 12 showed good dual-target bioactivities against RAGE (IC 50 = 8.26 ± 1.12 μM) and SERT (IC 50 = 31.09 ± 5.15 nM) in vitro , better safety profile than azeliragon, good liver microsomal stability, weak CYP inhibition, and acceptable pharmacokinetic properties. Moreover, 12 ameliorated Aβ 25-35 -induced neurotoxicity in SH-SY5Y cells and alleviated the depressive symptom in tail suspension test. In brief, these results indicated that 12 is a prospective prototype for the potential treatment of AD with comorbid depression. [Display omitted] • A novel therapeutic strategy of RAGE/SERT inhibitors for the treatment of AD with comorbid depression was firstly proposed. • Multiple vilazodone-azeliragon chimeric derivatives were designed, synthesized and evaluated as dual RAGE/SERT inhibitors. • Compound 12 showed good RAGE/SERT inhibitory activities and better safety profile than azeliragon. • Compound 12 exhibited significant neuroprotective effect against Aβ 25-35 -induced neuronal damage and alleviated depressive behavior of mice. [ABSTRACT FROM AUTHOR]

Abstract: A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimer’s disease is presented. [Copyright &y& Elsevier]

Abstract: The synthesis and the biological activities of new derivatives 1–3, characterized by the isothiocyanate (ITC) functionalities coming from sulforaphane (SFN), a well-known anticancer natural product, were reported. The most interesting compound of the series was 2. It was chemically characterized by two ITC functionalities mounted on the 1,4,5,8-naphthalentetracarboxylic diimide (NDI) scaffold through two polymethylene chains, each constituted by three carbon units. It demonstrated an IC50 value in the submicromolar range, more potent than SFN, displaying also the ability to trigger apoptotic induction in the same range by eliciting both extrinsic and intrinsic apoptotic pathways. Finally, it was observed that 2 inhibited the cell growth by blocking the cell cycle in G1 phase. [Copyright &y& Elsevier]

Abstract: A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H3R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H3R/AChE/BACE 1 (H3R antagonism, IC50 =280.0±98.0nM; H3R inverse agonism, IC50 =189.3±95.7nM; AChE, IC50 =483±5nM; BACE 1, 46.64±2.55% inhibitory rate at 20μM) and high selectivity over H1R/H2R/H4R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes. [Copyright &y& Elsevier]

With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1 – 4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by 1H NMR, 13C NMR, MS and elemental analysis. 1 – 4 showed inhibitory activities on reactive oxygen species, Aβ 1-42 aggregation (self-, Cu2+-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1 – 4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1 − 4 have also been synthesized. 1 – 4 selectively chelated Cu2+, Fe2+, Zn2+ and Al3+ ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1 −Cu(II) complex [Cu(C 19 H 18 NO 4) 2 ] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1 −Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aβ 1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics. [Display omitted] • A series of chrysin derivatives were designed and synthesized. • 1 – 4 show potent antioxidative, Aβ 1–42 disaggregation, selective anti-ChE activities. • The single crystal of 1 −Cu(II) was prepared and X-ray diffracted for the first time. • X-ray analysis provides a reliable structure-activity insight at the molecular level. • 1 – 4 have high BBB permeability and bioavailability and 1 has low cell toxicity. [ABSTRACT FROM AUTHOR]

Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT 1A receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT 1A receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro , low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression. [Display omitted] • A novel therapeutic strategy of Vil-Don chimeras for the treatment of AD with comorbid depression was firstly proposed. • Numerous MTDLs were designed and synthesized, their target activity against AChE/5-HT 1A /SERT were systematically evaluated. • The optimal compound 5 (5 mg/kg) could alleviate depressive symptom and ameliorate cognitive dysfunction in mouse models. • The pharmacophore fusion strategy has universal guiding significance in the development of new drugs for comorbid diseases. [ABSTRACT FROM AUTHOR]

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer's disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs [ABSTRACT FROM AUTHOR]

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC 50 = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC 50 = 2.91 ± 0.47 μM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 μM concentration. Furthermore, possessing significant self-mediated Aβ 1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood–brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents. [Display omitted] • Compound a8 possessed excellent inhibitory for BuChE and neuroinflammatory. • Compound a8 displayed self-mediated Aβ aggregation inhibition. • Compound a8 remarkably blocks the NF-κB signaling pathway. • Compound a8 could inhibit ROS formation and chelate Cu2+. • Compound a8 improved cognitive impairment in scopolamine-induced AD mice model. [ABSTRACT FROM AUTHOR]

[Display omitted] • The twin Drug of diosgenin derivatives were designed and synthesized. • Compound ML5 showed excellent protection in oxygen-glucose deprivation (OGD) cells. • Compound ML5 showed appropriate inhibition of cholinesterases (ChEs) in vivo. • Compound ML5 promoted the nuclear translocation of Nrf2 and showed strong antioxidant capacity. • Compound ML5 has significant neuroprotective effect in bilateral common carotid artery occlusion (BCCAO) rats by activation of Nrf2 and inhibition of ChEs. A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment. [ABSTRACT FROM AUTHOR]

• A novel series of 4-(Diethylamino)-Salicylaldehyde (3a-p) thiosemicarbazones was synthesized and characterized. • Probed as cholinesterase, carbonic anhydrase and α-Glycosidase Inhibitors. • SAR showed that aryl halides and hydroxybenzylidene moieties are critical for inhibition of enzymes. • In silico , molecular docking was carried out to study binding of active compounds with enzymes. • Pharmacokinetic properties of the most active novel compounds. With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated K i s varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b , 3k , and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b , 3g , 3k , and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of AChE/GSK-3β and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3β inhibition (h AChE IC 50 = 1.2 ± 0.1 nM; h GSK-3β IC 50 = 22.2 ± 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1α and DYRK1β at a concentration of 20 μM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of tau protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer's disease. Image 1 • A series of thiazolopyridyl tetrahydroacridines have been synthesized as AChE and GSK-3 dual inhibitors. • Potent nanomolar AChE/GSK-3β inhibitors were achieved. • The most promising hybrid have high kinase selectivity profiles for the CMGC kinase family. • The most active compounds displayed low toxicity in biological assays. • Demonstrated reversal of scopolamine-induced learning and memory impairment in ICR mice. [ABSTRACT FROM AUTHOR]

Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N -alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC 50 = 7.31 μM), BChE (IC 50 = 0.56 μM) and MAO-B (IC 50 = 26.1 μM) inhibitor 10 , dual AChE (IC 50 = 2.25 μM) and BChE (IC 50 = 0.81 μM) inhibitor 22 , selective BChE (IC 50 = 0.06 μM) inhibitor 13 , and selective MAO-B (IC 50 = 0.18 μM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10 , 13 , and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N -propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N -benzylpiperidine 10 is reversible. Additionally, compounds 10 , 13 , 16 , and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid β 1–42 (Aβ 1–42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ 1–42 anti-aggregation effects. Image 1 • Novel N -alkylpiperidine carbamates were designed, synthesized and bioevaluated. • Compound 10 inhibits cholinesterases, monoamine oxidase B and is neuroprotective. • Compound 13 is a potent selective butyrycholinesterase inhibitor. • Neuroprotective compound 16 inhibits monoamine oxidase B and amyloid β aggregation. • Compound 22 inhibits both acetylcholinesterase and butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD. [ABSTRACT FROM AUTHOR]

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aβ activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 μM) and cellular damage induced by H 2 O 2 (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 μM) or Aβ (astrocytes protection = 70.2 ± 6.5%, 10 μM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aβ 42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1β, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H 2 O 2 -induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aβ activities. Image 1 • Design and synthesis of diosgenin carbamate derivatives. • Biological evaluation and structure-activity relationships of these compounds. • Binding between M15 to nNOS, Aβ42 and pro-inflammatory proteins predicted by molecular docking. • M15 possesses antioxidant, anti-inflammatory and anti-Aβ toxicity activities. • M15 is a potential multifunctional neuroprotective agent. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with concealed onset, which is characterized by the damage of the cholinergic system, deposition, and accumulation of β- amyloid protein (Aβ) and neurofibrillary tangles. Because the cholinergic system plays a key role in the process of brain memory, it has become one of the important targets in anti-AD research. In view of the complicated pathological characteristics of AD, the multi-target directed ligands (MTDLs) that can act on multiple targets are considered to be an effective treatment strategy at present. Tacrine, as the first acetylcholinesterase (AChE) inhibitor, has been discontinued because of its hepatotoxicity, but its core structure is simple and easy to modify. By using tacrine to target the active catalytic site (CAS), the tacrine-based MTDLs can act on both CAS and peripheral anion site (PAS) of AChE to serve as a dual-site AChE inhibitor. Additionally, the tacrine-based MTDLs can also be designed on the basis of other theories of AD, for example, introducing functional moieties to modulate the formation of β-amyloid (Aβ), oxidation resistance, or metal chelation. In this paper, the research progress of tacrine-based MTDLs is summarized., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Increasing human life expectancy prompts the development of novel remedies for cognitive decline: 44 million people worldwide are affected by dementia, and this number is predicted to triple by 2050. Acetylcholinesterase and N -methyl-d-aspartate receptors represent the targets of currently available drugs for Alzheimer's disease, which are characterized by limited efficacy. Thus, the search for therapeutic agents with alternative or combined mechanisms of action is wide open. Since variations in 3',5'-cyclic adenosine monophosphate, 3',5'-cyclic guanosine monophosphate, and/or nitric oxide levels interfere with downstream pathways involved in memory processes, evidence supporting the potential of phosphodiesterase (PDE) inhibitors in contrasting neurodegeneration should be critically considered. For the preparation of this Review, more than 140 scientific papers were retrieved by searching PubMed and Scopus databases. A systematic approach was adopted when overviewing the different PDE isoforms, taking into account details on brain localization, downstream molecular mechanisms, and inhibitors currently under study, according to available in vitro and in vivo data. In the context of drug repurposing, a section focusing on PDE5 was introduced. Original computational studies were performed to rationalize the emerging evidence that suggests the role of PDE5 inhibitors as multi-target agents against neurodegeneration. Moreover, since such compounds must cross the blood-brain barrier and reach inhibitory concentrations in the central nervous system to exert their therapeutic activity, physicochemical parameters were analyzed and discussed. Taken together, literature and computational data suggest that some PDE5 inhibitors, such as tadalafil, represent promising candidates.

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H 3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H 3 R and both enzymes. Two derivatives were chosen - 5 (IC 50 = 0.46 μM (AChE); 0.44 μM (BuChE); K i = 159.8 nM (H 3 R)) and 17 (IC 50 = 0.50 μM (AChE); 0.76 μM (BuChE); K i = 228.2 nM (H 3 R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents. Image 1 • The library of histamine H 3 receptor ligands was prepared. • Docking-based virtual screening enabled to select multitarget compounds. • Cholinesterase inhibitory activity of selected hits was confirmed by Ellman's assay. • The most promising compounds displayed submicromolar activity toward all targets. [ABSTRACT FROM AUTHOR]

• Novel ferulic acid derivatives containing the benzylamino and carbamyl pharmacophores were designed and synthesized. • Compound 4g presented the greatest ability to inhibit cholinesterase (IC 50 , 19.7 nM for h AChE and 0.66 μM for h BuChE), good A β aggregation inhibition (49.2% at 20 μM) and good antioxidant activity (1.26 trolox equivalents). • Compound 4g had neuroprotection on H 2 O 2 -induced and A β -induced PC12 cells damage and could cross the BBB. A series of new ferulic acid derivatives were designed, synthesized and evaluated as multi-target inhibitors against Alzheimer's disease. In vitro studies indicated that most compounds showed significant potency to inhibit self-induced β -amyloid (A β) aggregation and acetylcholinesterase (AChE), and had good antioxidant activity. Specifically, compound 4g exhibited the potent ability to inhibit cholinesterase (ChE) (IC 50 , 19.7 nM for h AChE and 0.66 μM for h BuChE) and the good A β aggregation inhibition (49.2% at 20 μM), and it was also a good antioxidant (1.26 trolox equivalents). Kinetic and molecular modeling studies showed that compound 4g was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Moreover, compound 4g could remarkably increase PC12 cells viability in hydrogen peroxide–induced oxidative cell damage and A β -induced cell damage. Finally, compound 4g had good ability to cross the BBB using the PAMPA–BBB assay. These results suggested that compound 4g was a promising multifunctional ChE inhibitor for the further investigation. [ABSTRACT FROM AUTHOR]

A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes. [ABSTRACT FROM AUTHOR]

• Cholinesterase inhibition ability of fifty histamine H3 receptor ligands was assessed in vitro. • Four promising multi-target-directed ligands were discovered. • Chosen ligands displayed high drug-likeness and good blood–brain barrier penetration. • Binding mode of the most active compounds was explained by molecular docking. • Procognitive effect in passive avoidance test was revealed. In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4- n -propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4- n -propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood–brain barrier penetration in test conditions. The most promising compound, A12 , chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA 2 = 8.27), inhibitory activity against both AChE (IC 50 = 13.96 μM), and BuChE (IC 50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) enzyme and myeloid differentiation 2 protein (MD2) are two critical proteins involved in Alzheimer's disease (AD). Since the nature of the active site of AChE and the binding pocket of MD2 are similar, some ligands can inhibit both of them appropriately. Oxidative stress has also been known as an important cause of AD. Designing an effective common inhibitor with antioxidant activity to inhibit AChE and MD2 proteins is the main goal of this work. In this regard, we used tacrine molecule with a high ligand efficiency (LE) and dehydrozingerone (DHZ) with anti-inflammatory, antioxidant and anti-Alzheimer activities. Some modifications on DHZ structure can increase its antioxidant activity. So, tacrine molecule was combined with modified DHZ to present a new multi-target-directed ligand (MTDL). The ability of the designed ligand to inhibit AChE and MD2 proteins was confirmed by molecular docking, molecular dynamics (MD) simulation, and binding-free energy calculations. Therefore, the designed ligand can target two proteins involved in AD. It can also act as a potent antioxidant. In general, three important causative agents of AD are targeted by the designed ligand. Moreover, the inhibition of MD2, as the main source of oxidative stress, significantly reduces the production of free radicals.

Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. First, a hierarchical virtual screening was performed followed by biochemical evaluation of highest scoring hit compounds. Three compounds showed significant inhibitory activities against BChE and the best inhibitor was selected for further SAR studies. More than 100 different analogues were synthesized and among them, two compounds were found to be promising lead compounds as they were not cytotoxic, they crossed the blood-brain barrier and improved memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. The solved crystal structures of human BChE in complex with the most potent inhibitors revealed their binding modes and provided the structural basis for their further development into multitarget- directed ligands, which in addition to good inhibition of BChE possess good antioxidant, metal chelating, neuroprotective and other properties beneficial for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD), affecting a large population worldwide is characterized by the loss of memory and learning ability in the old population. The enzyme Acetylcholinesterase Enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity has been focused in recent years. Literature search was conducted for the molecules and their rational design which have shown inhibition for AChE and the other abovementioned targets. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. It is followed by optimization of the activity through structural modifications guided by structure-activity relationship studies. It has led to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other abovementioned targets for further pre-clinical studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC 50 of 0.271 ± 0.012 to 1.006 ± 0.075 μM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aβ aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.

Alzheimer's Disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive impairments and chronic inflammation that affects over 30 million people all over the world. Most of the Alzheimer's patients also suffer from psychosis, aggression, agitation, depression, anxiety, and many other behavioral and psychological symptoms of dementia. Unfortunately, the currently available anti-AD drugs provide modest symptomatic relief, and they do not reverse the neurodegeneration. Therefore, the average life expectancy after diagnosis is between six and ten years. Research data suggest that multi-target-directed ligands (MTDLs) give an opportunity to prevent, halt, or reverse the progression of AD, and reduce the symptoms of the disease. The aim of this review is to update the most recent reports on the development of MTDLs affecting serotonergic neurotransmission as potential drugs for both symptomatic and disease-modifying therapy of AD. Multifunctional modulators of serotonergic system exerted procognitive, antipsychotic, antidepressant, and/or anxiolytic properties in preclinical studies. Some of them revealed their potential as modulators of tau phosphorylation or amyloid beta aggregation with neuroprotective, anti-inflammatory, and/or antioxidant properties. Among them, lumateperone - an inhibitor of serotonin transporter with a high affinity for serotonergic and dopaminergic receptors is currently being tested in clinical trials in patients with dementia, bipolar depression, or schizophrenia. The high therapeutic potential of MTDLs as anti-AD drugs seems to be the result of their involvement in multiple neurotransmitter systems and intracellular signaling pathways., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Alzheimer's Disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (Aβ) oligomers formation and Aβ fibril deposition. Multi-Target- Directed Ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent Reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds. The biological diversity of MCRs is very rich providing great possibilities for researchers interested in bioactive small molecular weight compounds. Since the MTDL strategy has been used to develop compounds endowed with the capacity to interact with different targets, versatile compound libraries may be obtained by MCRs according to the well established features of each target. Thus, either MTDLs or monotarget compounds have been developed by MCRs to address different factors implicated in AD. This work focuses on antioxidants, calcium channel modulators, both AChE and BuChE inhibitors, BACE1 inhibitors, and modulators of the nuclear factor (erythroid-derived 2)-like 2. First, we discuss the Biginelli reaction and its use for developing new interesting compounds for AD, followed by the contribution of Ugi reaction and, finally, the interest of other MCRs in the same topic., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)