Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid beta (A beta 40) aggregation, were evaluated for the inhibition of tau protein ag-gregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared com-parable low micromolar inhibitory potency versus A beta 40 aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and A beta 40 aggregation with IC50 = 1.8 and 1.3 mu M, respectively. Moreover, at 0.1-10 mu M it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and A beta aggre-gation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC50 = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.

Automated summary

A set of thioxanthene-9-one and xanthene-9-one derivatives were evaluated for their inhibition of tau protein aggregation. Compound 20 showed outstanding biological data with inhibitory potency against tau protein and A beta 40 aggregation, and also exhibited neuroprotective activity. Compound 10 demonstrated good inhibition of cholinesterases with low cytotoxicity. Compound 4 showed high potency as a butyrylcholinesterase inhibitor with selectivity against acetylcholinesterase. These findings suggest that thioxanthene-9-one derivatives have the potential for AD therapy, pending further structural variations to improve safety.