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

  • J Med Chem. 2022 Mar 10;65(5):3962-3977. doi: 10.1021/acs.jmedchem.1c01784.
Mariagrazia Rullo  1 ,  Marco Cipolloni  2 ,  Marco Catto  1 ,  Carolina Colliva  2 ,  Daniela Valeria Miniero  3 ,  Tiziana Latronico  3 ,  Modesto de Candia  1 ,  Tiziana Benicchi  2 ,  Anna Linusson  4 ,  Nicola Giacchè  2 ,  Cosimo Damiano Altomare  1 ,  Leonardo Pisani  1
Affiliations
  • 1. Department of Pharmacy─Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy.
  • 2. TES Pharma s.r.l., Corso Vannucci 47, 06121 Perugia, Italy.
  • 3. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", via Orabona, 4, 70125 Bari, Italy.
  • 4. Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
PMID: 35195417 DOI: 10.1021/acs.jmedchem.1c01784
Abstract

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.

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