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.

Cyclocondensation of thiosalicylic acid (I) with p‐chlorotoluene (II) in sulfuric acid gives a mixture of the thioxanthen‐9‐ones (III) and (IV).

New Benzamide-Derived 5-HT3 Receptor Antagonists which Prevent the Effects of Ethanol on Extracellular Dopamine, and Fail to Reduce Voluntary Alcohol Intake in Rats -(design of substituted benzamides bearing a quinolizidine moiety (cf. ( I), (II)) and binding assays for 5-HT3 and D2 receptors). -(IUSCO, G.; BOIDO, V.; SPARATORE, F.; COLOMBO, G.; SABA, P. L.; ROSSETTI, Z.; VACCARI, A.; Farmaco