Multitarget Therapeutic Leads for Alzheimer's Disease: Quinolizidinyl Derivatives of Bi- and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β-Amyloid (Aβ) Aggregation.
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.
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy). michele.tonelli@unige.it.
Michele
M
Tonelli
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", V. Orabona 4, 70125 Bari (Italy). marco.catto@uniba.it.
Marco
M
Catto
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Bruno
B
Tasso
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Federica
F
Novelli
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Caterina
C
Canu
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Giovanna
G
Iusco
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", V. Orabona 4, 70125 Bari (Italy).
Leonardo
L
Pisani
Istituto di Virologia Vegetale del CNR, Università degli Studi di Bari "Aldo Moro", V. Amendola 165A, 70126 Bari (Italy).
Angelo De
AD
Stradis
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", V. Orabona 4, 70125 Bari (Italy).
Nunzio
N
Denora
Dipartimento di Scienze Farmaceutiche "P. Pratesi", Università degli Studi di Milano, V. Mangiagalli 25, 20133 Milano (Italy).
Anna
A
Sparatore
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Vito
V
Boido
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", V. Orabona 4, 70125 Bari (Italy).
Angelo
A
Carotti
Dipartimento di Farmacia, Università degli Studi di Genova, V. le Benedetto XV, 3, 16132 Genova (Italy).
Fabio
F
Sparatore
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001812:Blood-Brain Barrier; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D054837:Quinolizidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D054837:Quinolizidines
amyloid-beta; cholinesterases; multitarget agents; quinolizidines; quinonic derivatives; thioxanthenones