Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation |
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Authors: | Dr Michele Tonelli Dr Marco Catto Dr Bruno Tasso Dr Federica Novelli Dr Caterina Canu Dr Giovanna Iusco Dr Leonardo Pisani Dr Angelo De Stradis Dr Nunzio Denora Prof Anna Sparatore Prof Vito Boido Prof Angelo Carotti Prof Fabio Sparatore |
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Affiliation: | 1. Dipartimento di Farmacia, Università degli Studi di Genova, V. le?Benedetto?XV, 3, 16132 Genova (Italy);2. Dipartimento di Farmacia‐Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, V. Orabona?4, 70125 Bari (Italy);3. Istituto di Virologia Vegetale del CNR, Università degli Studi di Bari “Aldo Moro”, V. Amendola?165A, 70126 Bari (Italy);4. Dipartimento di Scienze Farmaceutiche “P. Pratesi”, Università degli Studi di Milano, V. Mangiagalli?25, 20133 Milano (Italy) |
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Abstract: | Multitarget therapeutic leads for Alzheimer’s disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β‐amyloid (Aβ) oligomerization. Thirty‐seven thioxanthen‐9‐one, xanthen‐9‐one, naphto‐ and anthraquinone derivatives were tested for the direct inhibition of Aβ(1–40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi‐ and tri‐cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β‐amyloid. In most cases, IC50 values were in the low micromolar and sub‐micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50=0.84 μM ) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics. |
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Keywords: | cholinesterases amyloid‐beta multitarget agents quinolizidines quinonic derivatives thioxanthenones |
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