Benzofuran and Benzo[b]thiophene-2-Carboxamide Derivatives as Modulators of Amyloid Beta (Aβ42) Aggregation.

A group of N-phenylbenzofuran-2-carboxamide and N-phenylbenzo[b]thiophene-2-carboxamide derivatives were designed and synthesized as a novel class of Aβ42 aggregation modulators. In the thioflavin-T based fluorescence aggregation kinetics study, compounds 4 a, 4 b, 5 a and 5 b possessing a methoxyphenol pharmacophore were able to demonstrate concentration dependent inhibition of Aβ42 aggregation with maximum inhibition of 54 % observed for compound 4 b. In contrast, incorporation of a 4-methoxyphenyl ring in compounds 4 d and 5 d led to a significant increase in Aβ42 fibrillogenesis demonstrating their ability to accelerate Aβ42 aggregation. Compound 4 d exhibited 2.7-fold increase in Aβ42 fibrillogenesis when tested at the maximum concentration of 25 μM. These results were further confirmed by electron microscopy studies which demonstrates the ability of compounds 4 a, 4 b, 4 d, 5 a, 5 b and 5 d to modulate Aβ42 fibrillogenesis. Compounds 5 a and 5 b provided significant neuroprotection to mouse hippocampal neuronal HT22 cells against Aβ42-induced cytotoxicity. Molecular docking studies suggest that the orientation of the bicyclic aromatic rings (either benzofuran or benzo[b]thiophene) plays a major role in moderating their ability to either inhibit or accelerate Aβ42 aggregation. Our findings support the application of these novel derivatives as pharmacological tools to study the mechanisms of Aβ42 aggregation.