Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

A novel series of
hybrid molecules were designed and synthesized
by fusing the pharmacophoric features of cholinesterase inhibitor
donepezil and diarylthiazole as potential multitarget-directed ligands
for the treatment of Alzheimer’s disease (AD). The compounds
showed significant in vitro anticholinesterase
(anti-ChE) activity, the most potent compound (44) among
them showing the highest activity (IC50 value of 0.30 ±
0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE.
Compound 44 showed mixed inhibition of AChE in the enzyme
kinetic studies. Some compounds exhibited moderate to high inhibition
of AChE-induced Aβ1–42 aggregation and noticeable
in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities.
Furthermore, compound 44 demonstrated in vivo neuroprotection
by decreasing Aβ1–42-induced toxicity by attenuating
abnormal levels of Aβ1–42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up
to 2000 mg/kg, po, dose without showing toxic effects.