Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease

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.     

Novel multitarget-directed tacrine derivatives as potential candidates for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is complex and progressive; it has not only threatened the health of elderly people, but also burdened the whole social medical and health system. The available therapy for AD is limited and the efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the design and development of efficacious and safe anti-AD agents has become a hotspot in the field of pharmaceutical research. Due to the multifactorial etiology of AD, the multitarget-directed ligands (MTDLs) approach is promising in search for new drugs for AD. Tacrine, which is the first acetylcholinesterase (AChE) inhibitor, has been selected as the ideal active fragment because of its simple structure, clear activity, and its superiority in the structural modification, thus it could be introduced into the overall molecular skeletons of the multi-target-directed anti-AD agents. In this review, we have summarized the recent advances (2012 to the present) in the chemical modification of tacrine, which could provide the reference for the further study of novel multi-target-directed tacrine derivatives to treat AD.     

From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease

Parkinson’s disease (PD) is the most common movement disorder. The neuropathology is characterized by the loss of dopamine neurons in the substantia nigra pars compacta. Transplants of fetal/embryonic midbrain tissue have exhibited some beneficial clinical effects in open-label trials. Neural grafting has, however, not become a standard treatment for several reasons. First, the supply of donor cells is limited, and therefore, surgery is accompanied by difficult logistics. Second, the extent of beneficial effects has varied in a partly unpredictable manner. Third, some patients have exhibited graft-related side effects in the form of involuntary movements. Fourth, in two major double-blind placebo-controlled trials, there was no effect of the transplants on the primary endpoints. Nevertheless, neural transplantation continues to receive a great deal of interest, and now, attention is shifting to the idea of using stem cells as starting donor material. In the context of stem cell therapy for PD, stem cells can be divided into three categories: neural stem cells, embryonic stem cells, and other tissue-specific types of stem cells, e.g., bone marrow stem cells. Each type of stem cell is associated with advantages and disadvantages. In this article, we review recent advances of stem cell research of direct relevance to clinical application in PD and highlight the pros and cons of the different sources of cells. We draw special attention to some key problems that face the translation of stem cell technology into the clinical arena.     

Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease

Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aβ_x-40 levels in FVB mice via a single 100 mpk IP dose are highlighted.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

Kinase signaling pathways as potential targets in the treatment of Parkinson’s disease

Parkinson’s disease (PD) is a severe, progressive, age-associated, neurodegenerative disorder. Current therapies are symptomatic and not effective at halting or significantly slowing the disease progress. The search for etiologic-based therapies has focused largely on genetic findings made in familial forms of this disease. Mutations of five genes have been unequivocally linked to PD; two of these, LRRK2 and PINK1, encode kinases and as such are attractive tools with which to understand the disease process; furthermore, preliminary functional data suggests that these proteins, or the pathways in which they are involved, are viable therapeutic targets. Here we explore the current data and thoughts regarding LRRK2 and PINK1 and discuss further avenues of research to understand the pathologic effects of mutations at these loci and potential points of therapeutic intervention, such as within these kinases or in associated pathways such as Jun N-terminal kinase and Akt pathways.     

Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.     

Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer’s disease

The optimization of our previous lead compound 1 (AChE IC₅₀ = 3.31 μM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC₅₀ = 2.57 μM), 6b (IC₅₀ = 0.70 μM) and 6i (IC₅₀ = 2.56 μM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC₅₀ = 1.11 μM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE–carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE–carbamate Michaelis complexes have been investigated.     

Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent disease of old age leading to dementia. Complex AD pathogenesis involves multiple factors viz. amyloid plaque formation, neurofibrillary tangles and inflammation. Herein we report of a new series of quinoxaline-bisthiazoles as multitarget-directed ligands (MTDLs) targeting BACE-1 and inflammation concurrently. Virtual screening of a library of novel quinoxaline-bisthiazoles was performed by docking studies. The most active molecules from the docking library were taken up for synthesis and characterized by spectral data. Compounds 8a-8n showed BACE-1 inhibition in micro molar range. One of the compounds, 8n showed BACE-1 inhibition at IC₅₀ of 3 ± 0.07 µM. Rat paw edema inhibition in acute and chronic models of inflammation were obtained at 69 ± 0.45% and 55 ± 0.7%, respectively. Compound 8n also showed noteworthy results in AlCl₃ induced AD model. The treated rats exhibited excellent antiamnesic, antiamyloid, antioxidant, and neuroprotective properties. Behavioural parameters suggested improved cognitive functions which further validates the testimony of present study. Moreover, compound 8n was found to have inherent gastrointestinal safety. This new string of quinoxaline-bisthiazoles were identified as effective lead for the generation of potent MTDLs and compound 8n was found to showcase qualities to tackle AD pathogenesis.     

Design,synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer’s disease

A series of chalcone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease based on the multi-target directed ligands design strategy. In vitro assays demonstrated that most of the derivatives exerted potent selective inhibitory potency on AChE with good multifunctional properties. Among them, representative compound 7c exhibited moderate inhibitory potency for EeAChE (IC₅₀ = 0.44 μM) and MAO-B inhibition (IC₅₀ = 1.21 μM), good inhibitory effect on self-induced Aβ₁₋₄₂ aggregation (55.0%, at 25 μM), biometal chelating property, moderate antioxidant activity with a value 1.93-fold of Trolox. Moreover, both kinetic analysis of AChE inhibition and molecular modeling study revealed that 7c showed a mixed-type inhibition, binding simultaneously to CAS and PAS of AChE. In addition, 7c also displayed high BBB permeability. These properties indicated 7c may be a promising multifunctional agent for the treatment of AD.     

New cyclopentaquinoline hybrids with multifunctional capacities for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of β-amyloid (Aβ), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment. Afterwards self-induced amyloid beta aggregation, inhibition studies of acetylcholinesterase and butyrylcholinesterase and molecular docking studies were performed. The results showed that 3b compound exhibited the best acetylcholinesterase inhibitory activity, with IC₅₀ value of 0.052?µM which is lower compared to references. Besides, all synthesised compounds showed good butyrylcholinesterase inhibitory activity with IC₅₀ values from 0.071 to 0.797?µM. Compound 3b exhibited strong Aβ_1–42 aggregation inhibitory effect with 25.7% at 5?µM to 92.8% at 100?µM as well as good anti-inflammatory effect. Thus, new compounds could create new perspectives for further development as a multi-target-directed agent for AD treatment.     

Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer’s disease

A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aβ aggregation, metal-induced Aβ aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF₃ group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC₅₀ = 8.065 ± 0.129 μM) against Aβ₄₂ aggregation, compared to the reference compound curcumin (95.14% inhibition, IC₅₀ = 6.385 ± 0.009 μM). Compound 6n disassembled preformed Aβ₄₂ aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu²⁺-induced Aβ₄₂ aggregation and disassembled preformed Cu²⁺-induced Aβ₄₂ aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aβ₄₂ aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aβ₄₂ monomer and Aβ₄₂ protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aβ₄₂ that play a critical role in Aβ₄₂ aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.     

Medicinal herbs and antioxidants: potential of Rhinacanthus nasutus for disease treatment?

This review covers the biological activities of the medicinal herb, Rhinacanthus nasutus, which is part of the Acanthaceae family. This herb and the compounds isolated from it have the potential to be used for the treatment of a vast array of diseases, including neurological, (such as Alzheimer’s, Parkinson’s and depression), viral and bacterial infections (such as hepatitis and herpes virus), skin disorders, and control sugar levels in diabetic patients. Many diseases involve oxidative stress, particularly neurological diseases, where oxidative stress leads to neurodegeneration. Medicinal herbs such as R. nasutus appear to be effective at protecting against such oxidative stress. Herein we discuss the potential mechanisms by which they have their antioxidant effects, and their effects on other cellular pathways, which are involved in various disease states.     

Peroxiredoxins from Trypanosoma cruzi: virulence factors and drug targets for treatment of Chagas disease?

Cytosolic and mitochondrial Trypanosoma cruzi tryparedoxin peroxidases belong to the family of 2-Cys peroxiredoxins. These enzymes play an essential role as antioxidants by their peroxidase and peroxynitrite reductase activities. TXNPx are key components of the trypanosomatid peroxide detoxification pathways. The aim of this work was to determine the role of TXNPx as virulence factors in the parasite, and whether these enzymes are good candidates for drug design. We observed that peroxiredoxins are not highly abundant proteins expressed at similar levels throughout the T. cruzi life cycle. In order to study the role of c-TXNPx and m-TXNPx in invasion and infectivity, parasites overexpressing TXNPx were produced, and infection experiments were carried out using phagocytic and non-phagocytic cells. Parasites overexpressing peroxiredoxins showed a significant increase in infectivity with respect to the control ones. The results presented in this work point out that the T. cruzi peroxiredoxins are important in survival, replication and differentiation of T. cruzi and could constitute virulence factors. Moreover, their expression in the infective forms of the life cycle and their low intracellular concentration make them good candidates to become targets for drug design.     

Novel PDE5 inhibitors derived from rutaecarpine for the treatment of Alzheimer’s disease

A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure–activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC₅₀ values about 0.086 μM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer’s disease.     

That’s amore: Bone marrow cells compete for the heart in Chagas disease

Comment on: Soares MB, et al. Cell Cycle 2011; 10:1448-55.     

The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer’s disease (AD). Certain evidence exists that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of AD patients plays a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase (Smase), which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit SMase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer’s disease and monitoring the effectiveness of treatment with new drugs is discussed.     

Development of bivalent compounds as potential neuroprotectants for Alzheimer’s disease

In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC₅₀ of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease.     

Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer’s disease

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC₅₀?=?0.56?μM and 5.12?μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ_1–42 aggregation (IC₅₀?=?3.05?μM) and Cu²⁺-induced Aβ_1–42 aggregation (71.7% at 25.0?μM), and displayed significant disaggregation ability to self- and Cu²⁺-induced Aβ_1–42 aggregation fibrils (75.2% and 77.2% at 25.0?μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.