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

• DOI: 10.1021/acs.jmedchem.1c01784
• Publication Date: 2022-02-23T16:01:54Z
• Authors: Mariagrazia Rullo; Marco Cipolloni; Marco Catto; Carolina Colliva; Daniela Valeria M...; Tiziana Latronico; Modesto de Candia; Tiziana Benicchi; Anna Linusson; Nicola Giacchè; Cosimo Damiano Al...; Leonardo Pisani
• Keywords: 0301 basic medicine; Monoamine Oxidase Inhibitors; Dopamine Agents; 610; coumarin; Structure-Activity Relationship; 03 medical and health sciences; fluorine; 615; Drug Design; Acetylcholinesterase; Humans; Cholinesterase Inhibitors; multitarget; Caco-2 Cells; Monoamine Oxidase

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.