Rational Design of Multifunctional Tacrine Derivatives as Candidates for the Treatment of Alzheimer and Parkinson Diseases.

Alzheimer disease (AD) and Parkinson disease (PD) are multifactorial neurodegenerative disorders for which there is currently no therapy that prevents or slows their progress. Some drugs used to treat AD are inhibitors of acetylcholinesterase (AChE) and antagonists of N-methyl-D-aspartate receptor (NMDAr), while inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are used for PD. Tacrine was the first FDA (Food and Drug Administration) approved drug against AD. Although later withdrawn due to hepatotoxicity, it remains a pivotal scaffold for drug development. Herein, 1295 tacrine derivatives, meant to enhance therapeutic efficacy and safety of the parent compound, were designed through the CADMA-Chem protocol. The chemical space was screened using selection scores based on ADME properties, toxicity, and synthetic accessibility. Two derivatives with the best drug-like behavior were chosen for further investigation. Acid-base constants and reactivity descriptors were estimated for them. Our findings show that these derivatives are promising inhibitors of AChE, COMT, NMDAr, and MAO-B. Therefore, according to in silico predictions they are expected to be beneficial for AD and PD. One of the compounds investigated here is the first reported tacrine-derived compound with potential as COMT inhibitor.