ABSTRACT
The formation of amyloid-ß (Aß) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting Aß deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of Aß deposits in the brain. The probe had excellent fluorescent properties with an emission maximum above 720â¯nm upon binding to Aß aggregates with affinity of 445.0â¯nM (Kd). Furthermore, ZT-1 exhibited good biostability, photostability, and binding selectivity toward Aß1-42 aggregates by in vitro fluorescence staining experiments. In vivo NIRF imaging result also revealed that our probe could efficiently differentiate transgenic and wild-type mice. All these studies indicated that ZT-1 is a promising fluorescent probe for Aß plaques in the AD brains.
Subject(s)
Alzheimer Disease/diagnostic imaging , Carbocyanines/chemistry , Optical Imaging , Plaque, Amyloid/chemistry , Animals , Carbocyanines/chemical synthesis , Dose-Response Relationship, Drug , Infrared Rays , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Molecular Structure , Structure-Activity RelationshipABSTRACT
The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075⯵M for eeAChE and 0.75⯵M for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4⯵M for hMAO-B), excellent antioxidant activity (71.7⯵M of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aß aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12â¯cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.
Subject(s)
Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Cholinergic Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Butylated Hydroxytoluene/chemistry , Butylated Hydroxytoluene/pharmacology , Cell Line , Cholinergic Agents/chemical synthesis , Cholinergic Agents/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil , Dose-Response Relationship, Drug , Indans/chemistry , Indans/pharmacology , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Piperidines/chemistry , Piperidines/pharmacology , Protein Aggregates/drug effects , Rats , Structure-Activity RelationshipABSTRACT
A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
Subject(s)
Alzheimer Disease/drug therapy , Drug Design , Imines/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Salicylates/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Hydrogen Peroxide/pharmacology , Imines/chemical synthesis , Imines/chemistry , Ligands , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Microglia/drug effects , Microglia/metabolism , Molecular Docking Simulation , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , PC12 Cells , Peptide Fragments/antagonists & inhibitors , Protein Aggregates/drug effects , Rats , Salicylates/chemical synthesis , Salicylates/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.
