Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.

We have identified the compound 12d exhibiting potent inhibitory activity against amyloid beta-induced mPTP opening and possessing good safety and pharmacokinetic profile.Figure optionsDownload as PowerPoint slideHighlights
► New series of azacycle-containing oxime derivatives were synthesized.
► 12d effectively inhibited Abeta-induced mPTP opening.
► 12d showed high efficacies in mitochondrial functional assays (ATP, ROS, MTT).
► 12d exhibited good metabolic/plasma stabilities and PK profiles.