Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies

Bioisosteric
H/F or CH2OH/CF2H replacement
was introduced in coumarin derivatives previously characterized as
dual AChE-MAO B inhibitors to probe the effects on both inhibitory
potency and drug-likeness. Along with in vitro screening, we investigated
early-ADME parameters related to solubility and lipophilicity (Sol7.4, CHI7.4, log D7.4), oral bioavailability and central nervous system (CNS) penetration
(PAMPA-HDM and PAMPA-blood–brain barrier (BBB) assays, Caco-2
bidirectional transport study), and metabolic liability (half-lives
and clearance in microsomes, inhibition of CYP3A4). Both specific
and nonspecific tissue toxicities were determined in SH-SY5Y and HepG2
lines, respectively. Compound 15 bearing a −CF2H motif emerged as a water-soluble, orally bioavailable CNS-permeant
potent inhibitor of both human AChE (IC50 = 550 nM) and
MAO B (IC50 = 8.2 nM, B/A selectivity > 1200). Moreover, 15 behaved as a safe and metabolically stable neuroprotective
agent, devoid of cytochrome liability.