7-MEOTA–donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies

• Novel derivatives related to 7-methoxytacrine and donepezil were developed.
• N-benzylpiperazine moiety mimicking N-benzylpiperidine from donepezil was used.
• Derivatives exerted μM to sub-μM inhibition profile against cholinesterases.
• Derivatives are capable to simultaneously bind both sites of acetylcholinesterase.
• QSAR and docking studies rationalized results from in vitro.

A novel series of 7-methoxytacrine (7-MEOTA)–donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA–donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA–donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment.

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