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

• Published in: Journal of medicinal chemistry 2022-03, Vol.65 (5), p.3962-3977
• Main Authors: Rullo, Mariagrazia, Cipolloni, Marco, Catto, Marco, Colliva, Carolina, Miniero, Daniela Valeria, Latronico, Tiziana, de Candia, Modesto, Benicchi, Tiziana, Linusson, Anna, Giacchè, Nicola, Altomare, Cosimo Damiano, Pisani, Leonardo
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01784

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 D 7.4), 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.