Fluorinated benzophenone derivatives: Balanced multipotent agents for Alzheimer's disease

• A small chemical library of fluorinated benzophenone derivatives was designed and synthesized.
• The biological profile towards BACE-1, AChE and the ability to counteract intracellular ROS formation were evaluated.
• Compounds 5 and 12 showed potencies in the same range against the selected targets (balanced μM inhibitory activity).
• Computational studies performed on 5 and 12 within the BACE-1 active site supported the biological data.
• Derivative 12, completely devoid of toxic effects, represents a potential multitarget lead compound for Alzheimer's disease.

In an effort to develop multipotent agents against β-secretase (BACE-1) and acetylcholinesterase (AChE), able to counteract intracellular ROS formation as well, the structure of the fluorinated benzophenone 3 served as starting point for the synthesis of a small library of 3-fluoro-4-hydroxy- analogues. Among the series, derivatives 5 and 12, carrying chemically different amino functions, showed a balanced micromolar potency against the selected targets. In particular, compound 12, completely devoid of toxic effects, seems to be a promising lead for obtaining effective anti-AD drug candidates.

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