Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer''s disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe³⁺ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC₅₀ = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.     

Presenilins: multifunctional proteins involved in Alzheimer's disease pathology

Early-onset aggressive forms of Alzheimer's disease (AD) are of genetic nature and have been linked to inherited mutations located on chromosomes 21, 14, and 1. The gene products of chromosomes 14 and 1, which are responsible for most of these familial forms of the disease (FAD), have been recently identified and referred to as presenilin 1 and 2 (PS1, PS2), respectively. Several lines of evidence derived from neuropathological, cell biology, and transgenesis approaches indicate that PS could interfere with the processing of the beta-amyloid precursor protein (betaAPP). Thus, FAD-linked mutations in PS exacerbate the production of Abeta42, the readily aggregable Abeta species corresponding to one of the main constituents of the senile plaques that invade the cortical areas of affected brains. Recent studies indicate that PS functions could be intimately related with the susceptibility of PS to further processing by caspase-like enzymes and other unknown proteolytic activities. Here I briefly report on the post-translational events undergone by PS and examine recent advances concerning their possible roles in development, cell signaling, and apoptosis. Possible alterations brought by FAD-linked mutations will be discussed.     

Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design,synthesis and biological evaluation

A series of salicylamide 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 were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu²⁺-induced Aβ_1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC₅₀ value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu²⁺-induced Aβ_1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu²⁺-induced Aβ_1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.     

Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: application to a pyrimidine-2,4-diamine template

We investigated a group of 2-benzylpiperidin-N-benzylpyrimidin-4-amines with various electron-withdrawing or electron-donating groups (EWGs or EDGs, respectively) as multi-targeted Alzheimer's disease (AD) therapeutics. The synthesized derivatives were screened for anti-cholinesterase (AChE and BuChE), anti-Aβ-aggregation (AChE- and self-induced) and anti-β-secretase (BACE-1) activities in an effort to identify lead, multifunctional candidates as part of our multi-targeted approach to treat AD. Biological assessment revealed that the nature of the substituent on the C-4 benzylamine group (e.g., halogen vs methoxy-based) greatly affected the biological profile. In vitro screening identified N(2)-(1-benzylpiperidin-4-yl)-N(4)-(3,4-dimethoxybenzyl)pyrimidine-2,4-diamine (7h) as the lead candidate with a dual ChE (AChE IC(50)=9.9 μM; BuChE IC(50)=11.4 μM), Aβ-aggregation (AChE-induced=59.3%; self-induced=17.4% at 100 μM) and BACE-1 (34% inhibition at 10 μM) inhibitory profile along with good cell viability (% neuroblastoma cell viability at 40 μM=81.0%). Molecular modeling studies indicate that a central pyrimidine-2,4-diamine ring serves as a suitable template to develop novel small molecule candidates to target multiple pathological routes in AD.     

Design, synthesis, and biological evaluation of curcumin analogues as multifunctional agents for the treatment of Alzheimer's disease

A series of novel curcumin analogues were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of AD. The in vitro studies showed that these compounds had better inhibitory properties against Aβ aggregation than curcumin. Superior anti-oxidant properties (better than the reference compound Trolox) of these compounds were observed by the oxygen radical absorbance capacity (ORAC) method and a cell-based assay using DCFH-DA as a probe. In addition they were able to chelate metals such as iron and copper and decrease metal-induced Aβ aggregation. The structure-activity relationships were discussed. The results suggested that our curcumin analogues could be selected as multifunctional agents for further investigation of AD treatment.     

Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of β-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress.MethodsThe following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ_1–42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies.ResultsWe synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβ aggregation inhibitory activity. Compound 9g had 74% Aβ_1–42 aggregation inhibitory effect at 10 μM concentration with its IC₅₀ value of 6.5 μM for self-induced Aβ_1–42 aggregation. This compound also showed good inhibition of metal-mediated (Cu^2 + and Fe^2 +) and acetylcholinesterase-induced Aβ_1–42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC₅₀ values of 0.86 μM and 0.51 μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29.ConclusionsCompound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease.General significanceCompound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment.     

Velnacrine thiaanalogues as potential agents for treating Alzheimer's disease

The only therapeutic drugs for combating dementia disease are acetylcholine esterase inhibitors (AChEI). However, the use of tacrine, the first AChEI to be launched as an Alzheimer's disease (AD) drug, has been limited by serious side effects. Therefore, efforts to search for more potent and selective inhibitors of AChE still remain highly significant in the therapeutic treatment of AD. In this work we modified the cyclohexyl ring of velnacrine, a less toxic analogue of tacrine, by synthesizing a series of thiopyranoquinolines in which the C-3 methylene unit was replaced by a sulphur atom. The anti-AChE data show that the activity was maintained with the bioisosteric substitution carried out. The introduction of a chlorine atom at different positions of the aromatic ring resulted in an array of different activities. In an attempt to understand the different behaviours displayed by the chlorine-substituted derivatives, a molecular docking study was performed.     

Synthesis and evaluation of tacrine-E2020 hybrids as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease

Tacrine-E2020 hybrids and some related compounds were prepared and their bioactivities on the Alzheimer's disease were assayed. The optimum hybrid inhibitor 3 is 37-fold more potent and 31-fold more selective than tacrine in vitro.     

Development of naringenin-O-alkylamine derivatives as multifunctional agents for the treatment of Alzheimer’s disease

In this study, a series of naringenin-O-alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC₅₀ values of 0.91 μM and 0.57 μM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aβ_1–42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aβ_1–40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu²⁺-induced Aβ_1–42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.     

Albumin-bound polyacrolein: implications for Alzheimer's disease

Acrolein-modified proteins are markers of disorders such as Alzheimer's disease (AD). Acrolein (H2C=HC-CH=O), which can be produced by the oxidative properties of amyloid-beta (Abeta) peptide, localizes to areas immediately surrounding early Abeta aggregates. The focal production of acrolein would consequently yield localized high concentrations that may be susceptible to polymerization via basic latex polymer chemistry. Using albumin as our model we examined whether simple in vitro conditions may bring about higher order aggregates composed of polyacrolein. We observed that thin plastic-like fragments were formed following incubation of albumin in acrolein solutions from 5 to 500 mM in sodium phosphate buffers (pH 7.4). The layered plastic film stained for carbonyls and for amyloid (cross-beta structures) suggesting a polyacrolein-albumin colloidal mixture. Large structures (up to 2700 microm2) readily form under simple conditions. These observations suggest that polyacrolein latexes may potentially exist in biological tissues contributing to the pathogenesis of diseases such as AD.     

Therapy for Alzheimer's disease

Therapeutic strategies aimed to treat Alzheimer's disease (AD) may either produce an attenuation of symptoms or slowdown deterioration by attenuating progression of the disease. Presently, cholinesterase inhibitors (ChEI) have shown the most promising therapeutic effects. The best documented clinical efficacy of ChEI are studies of THA (tacrine, tetrahydroaminoacridine). The results of five recent studies in a total of 1,242 patients are discussed. Based on differences from placebo in scoring, a gain of 2–12 (MMSE) or 5–6 (ADAS) in deterioration can be seen for a THA treatment of 2–3 mo duration. This suggests that if treatment with THA will be extended to a longer period, the drug effect may not be only a symptomatic improvement but also a slowdown of disease course. A similarity of THA's effect in AD withl-deprenyl effects in Parkinson's is suggested.     

Coumarin hybrids as novel therapeutic agents

Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer’s disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure–activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.     

Strategies for disease modification in Alzheimer's disease

Treating Alzheimer's disease (AD) is the biggest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. Three main classes of disease-modification approaches can be defined: one that is broadly neurotrophic or neuroprotective, one that targets specific aspects of AD pathology, and one that is based on epidemiological observation. This review discusses all three approaches, with particular emphasis on anti-amyloid strategies - currently the most active area of investigation. The approaches that are reviewed include secretase inhibition, amyloid-beta aggregation inhibition, immunotherapy and strategies that might indirectly affect the amyloid pathway.     

Glycidol-carbohydrate hybrids: a new family of DNA alkylating agents

Novel and chiral glycidol-carbohydrate hybrids possessing an epoxy group as a DNA alkylating moiety were designed and synthesized. These artificial hybrids selectively alkylated DNA at the N-7 sites of the guanines and cleaved DNA without any additives. The binding ability of the glycidol was significantly enhanced by the attachment of the carbohydrate.     

Neuroendocrinology-based therapy for Alzheimer's disease

The nervous system interacts directly with the endocrine system to control a plethora of central nervous system (CNS) functions. Metabolic and reproductive hormones are known to be important in the maintenance of neuronal health and their fluctuations are important for CNS aspects ranging from sleep and appetite regulation to cognitive function. This review will summarize and critically evaluate how age-related changes in sex and metabolic hormones modulate affect cognitive function and the implications of targeting the neuroendocrinological system as a therapeutic strategy in Alzheimer's disease.