Design, synthesis, and pharmacological evaluation of indole-piperidine amides as Blood-brain barrier permeable dual cholinesterase and β-secretase inhibitors

Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC₅₀ values of 0.32 and 0.39 μM, respectively. The MTDL 23a is a mixed-type inhibitor of both hAChE and hBACE-1 with K_i values of 0.26 μM and 0.46 μM, respectively. The MD simulation studies revealed that both AChE and BACE-1 experience minor conformational changes on binding with 23a. In the PAMPA-BBB assay, analog 23a demonstrated CNS permeability, indicating the possibility for future investigation in preclinical models of AD.

Alzheimer's disease; Blood-brain barrier; Cholinesterase inhibitor; Heterocycles; Indole-piperidine amides.