Nilesh Gajanan Bajad, Gajendra T A, Khushboo Sharma, Madhu G Tapadia, Ashok Kumar, Sairam Krishnamurthy, Sushil Kumar Singh
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引用次数: 0
Abstract
The cholinergic deficits and deposition of β-amyloid (Aβ) species are regarded as the key events contributing to the progression of Alzheimer's disease (AD). Herein, a series of novel donor-acceptor architecture-type potential theranostic agents were designed, synthesized, and evaluated for their potential against cholinesterase (ChE) enzymes and detection of Aβ species, which are primary targets in the development of therapeutics for AD. The optimal compound/probe 18 containing a benzothiazolium fluorophore with a bifunctional electron-donating N-aryl piperazine scaffold exhibited potent inhibitory activities against acetylcholinesterase (AChE; IC50 = 0.172 ± 0.011 μM) and butyrylcholinesterase (BuChE; IC50 = 1.376 ± 0.141 μM). Measurement of fluorescence properties showed that probe 18 exhibited emission maxima (λem) of >610 nm in dimethyl sulfoxide (DMSO) and >590 nm in PBS, suitable for the fluorescence imaging. In vitro studies demonstrated a change in fluorescence characteristics and high binding affinities (18; Kd = 0.731 μM) upon binding with Aβ aggregates. The affinity of probe 18 toward Aβ aggregates was further observed in elavGAL4 > UAS Aβ, the Drosophila larval brain sections, using a fluorescence imaging technique. The in vivo acute oral toxicity evaluation indicated a safety profile of the lead probe 18. Moreover, in vivo behavioral studies including Y-maze and novel object recognition tests signified that the administration of compound 18 improved cognitive and spatial memory impairment at a dose of 10 and 20 mg/kg in the scopolamine-induced cognitive deficit model.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research