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.
Keywords: Alzheimer’s disease; Aβ aggregation; Drosophila; fluorescent probes; theranostic agents.