Bioisosteric H/F or CH<sub>2</sub>OH/CF<sub>2</sub>H 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 (Sol<sub>7.4</sub>, CHI<sub>7.4</sub>, log <i>D</i><sub>7.4</sub>), 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 <b>15</b> bearing a -CF<sub>2</sub>H motif emerged as a water-soluble, orally bioavailable CNS-permeant potent inhibitor of both human AChE (IC<sub>50</sub> = 550 nM) and MAO B (IC<sub>50</sub> = 8.2 nM, B/A selectivity > 1200). Moreover, <b>15</b> behaved as a safe and metabolically stable neuroprotective agent, devoid of cytochrome liability.