Synthesis and Biological Evaluation of Novel Fluorinated Tacrine Against Alzheimer\u27s Disease (AD)

Alzheimer’s disease (AD) remains an unmet medical need despite global efforts to identify drugs that are potent, safe and selective. Unfortunately, AD is a multifactorial disorder in which several factors impact both its etiology and pathogenesis. Decreased levels of acetylcholine (Ach), accumulation of beta-amyloid plaques and neurofibrillary tangles, including oxidative stress have been identified as symptoms of AD. Studies involving the inhibition of acetylcholinesterase, the enzyme that hydrolyzes Ach led to the approval of tacrine for the treatment of AD. Later, tacrine was found to be unselective, since it inhibits both AChE and butyrylcholinsterase (BuChE). In addition, tacrine was found to induce oxidative stress. These issues lead to our research to synthesize fluorinated tacrine derivatives to minimize the excessive side effects of THA. The primary objective of this study is to design novel fluorinated tacrine derivatives. We successfully synthesized and characterized seven fluorinated derivatives. All the compounds (6a - 6e) with the exception of the phenoxy derivatives were active against acetylcholinesterase during our preliminary studies. The inhibition kinetics of the two most active derivatives (6a and 6b) were further studied. The kinetic displayed increasing slope and increasing intercept, which is consistent with a mixed inhibition, as reported for tacrine. The IC50 and Ki values of 6a are 0.118 μm and 0.03. Compound 6b exhibited IC50 of 0.077 μm and Ki of 0.165. The above data compared favorably with data for tacrine (0.0486 μm and Ki, 0.217) the reference compound in our study