Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection.

Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer's disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aß) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aß aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aß inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aß- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.

Curcumin and a hemi-analogue with improved blood-brain barrier permeability protect against amyloid-beta toxicity in Caenorhabditis elegans via SKN-1/Nrf activation.

OBJECTIVES: This study aims to investigate the blood-brain barrier (BBB) permeability of curcumin analogues with shortened linkers and their ability to protect against amyloid-beta toxicity in a whole organism model. METHOD: Four curcumin analogues were synthesized. These analogues and curcumin were evaluated for their BBB permeability in the parallel artificial membrane permeability assay. The transgenic Caenorhabditis elegansGMC101 that expresses human Aß1-42 was treated with the compounds to evaluate their ability to delay Aß-induced paralysis. Expression of skn-1mRNA was examined on nematodes treated with selected efficacious compounds. In vitro Aß aggregation in the presence of the compounds was performed. KEY FINDINGS: The four analogues showed improved BBB permeability vs curcumin in the PAMPA with the hemi-analogue C4 having the highest permeability coefficient. At 100 µm, analogues C1 and C4 as well as curcumin significantly prolonged the survival of the nematodes protecting against Aß toxicity. However, only curcumin and C4 showed protection at lower concentrations. skn-1mRNA was significantly elevated in nematodes treated with curcumin and C4 indicating SKN-1/Nrf activation as a possible mode of action. CONCLUSIONS: Analogue C4 provides a new lead for the development of a curcumin-based compound for protection against Aß toxicity with an improved BBB permeability.