Exploring the structure-activity relationship of benzylidene-2,3-dihydro-1H-inden-1-one compared to benzofuran-3(2H)-one derivatives as inhibitors of tau amyloid fibers.

Tauopathies, such as Alzheimer's disease, have been the subject of several hypotheses regarding the way to treat them. Hyperphosphorylation of tau protein leading to its aggregation is widely recognized as a key step in the development of these diseases resulting in neuronal dysfunction. The AcPHF6 model of tau that includes the shorter critical fragment involved in the protein aggregation was used in vitro to identify new potential inhibitors. Following a previous study on aurone derivatives, we herein compare this polyphenol family to a very close one, the benzylidene-2,3-dihydro-1H-inden-1-one (also named indanone). The structure activity relationship studies bring to light the importance of the hydroxylation pattern in both series: the more hydroxylated, the more active. In addition, the three-dimensional shape of the molecules is involved in their interaction mode with their target, thus defining their role either as inhibitors of fiber elongation or as fiber-binding molecules. Indanone 13a was identified as a promising inhibitor: its activity was confirmed by circular dichroism and atomic force microscopy studies.

Interest of novel N-alkylpyridinium-indolizine hybrids in the field of Alzheimer's disease: Synthesis, characterization and evaluation of antioxidant activity, cholinesterase inhibition, and amyloid fibrillation interference.

A small library of molecules combining indolizine and N-alkyl pyridinium was synthesized and evaluated in a multi-target-directed-ligand strategy for Alzheimer's disease (AD) treatment. The new compounds were classified in three series depending on the number of methylene residues linking the two heterocycles (Ind-PyCx with x = 0, 2 or 3). The molecules were synthesized from the corresponding bis-pyridines by two-step formation of the indolizine core including mono-alkylation of pyridine and 1,3-dipolar cycloaddition with an alkylpropiolate. Their activities against AD's key-targets were evaluated in vitro: acetyl- and butyrylcholinesterase (AChE and BChE) inhibition, antioxidant properties and inhibition of amyloid fibril formation. None of the three series showed significant activities against all the targets. The Ind-PyC2 and Ind-PyC3 series are active on eeAChE and hAChE (µM IC50 values). Most of the positively charged molecules from these two series also appeared active against eqBChE, however they lost their activity on hBChE. Comparative molecular modeling of 13 and 15 docked in hAChE and hBChE highlighted the importance of the substituent (p-methoxybenzoyl or methyloxycarbonyl, respectively) located on the indolizine C-3 for the binding. The larger molecule 13 fits more tightly at the active site of the two enzymes than 15 that shows a larger degree of freedom. The Ind-PyC2 and Ind-PyC3 hybrids displayed some antioxidant activity when tested at 750 µg/mL (up to 95% inhibition of DPPH radical scavenging for 10). In both series, most hybrids were also able to interact with amyloid fibers, even if the inhibitory effect was observed at a high 100 µM concentration. The Ind-PyC0 molecules stand out completely due to their spectroscopic properties which prevent their evaluation by Ellman's and ThT assays. However, these molecules showed interesting features in the presence of preformed fibers. In particular, the strong increase in fluorescence of 3 in the presence of amyloid fibers is very promising for its use as a fibrillation fluorescent reporter dye.