Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated
mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models.
Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity
of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds
with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD
enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated
mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by
increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function
effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic
development to target ABAD to improve mitochondrial function.