Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

• DOI: 10.1002/cmdc.201500104
• Publication Date: 2015-04-29T20:43:35Z
• Authors: Michele Tonelli; Marco Catto; Bruno Tasso; Federica Novelli; Caterina Canu; Giovanna Iusco; Leonardo Pisani; Angelo De Stradis; Nunzio Denora; Anna Sparatore; Vito Boido; Angelo Carotti; Fabio Sparatore
• Keywords: Tricyclic; Amyloid (mycology)

Multitarget therapeutic leads for Alzheimer's disease were designed on the models of compounds capable maintaining or restoring cell protein homeostasis and inhibiting β-amyloid (Aβ) oligomerization. Thirty-seven thioxanthen-9-one, xanthen-9-one, naphto- anthraquinone derivatives tested direct inhibition Aβ(1-40) aggregation electric eel acetylcholinesterase (eeAChE) horse serum butyrylcholinesterase (hsBChE). These are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi- tri-cyclic (hetero)aromatic systems. With very few exceptions, these displayed inhibitory activity both AChE BChE spontaneous β-amyloid. In most cases, IC50 values in low micromolar sub-micromolar range, but some even reached nanomolar potency. The time course amyloid presence active derivative (IC50 =0.84 μM) revealed that might act as destabilizers mature fibrils rather than mere inhibitors fibrillization. Many inhibited one cholinesterases Aβ with similar potency, a fundamental requisite possible development therapeutics exhibiting multitarget mechanism action. described thus represent interesting AD therapeutics.