Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aβ deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimer's disease

Abstract

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aβ1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30, had IC50 values of 11.15 μM and 6.87 μM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aβ1-42 fibril aggregation and promoted fibril disaggregation with IC50 of 3.69 μM and 3.35 μM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aβ1-42, and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease.