2. Academic Validation
  3. Novel coumarin-pyridazine hybrids as selective MAO-B inhibitors for the Parkinson's disease therapy

Novel coumarin-pyridazine hybrids as selective MAO-B inhibitors for the Parkinson's disease therapy

  • Bioorg Chem. 2020 Nov:104:104203. doi: 10.1016/j.bioorg.2020.104203.
Fernanda Rodríguez-Enríquez 1,  María Carmen Costas-Lago 2,  Pedro Besada 2,  Miguel Alonso-Pena 2,  Iria Torres-Terán 1,  Dolores Viña 1,  José Ángel Fontenla 3,  Mattia Sturlese 4,  Stefano Moro 4,  Elias Quezada 5,  Carmen Terán 6
Affiliations

Affiliations

  • 1 Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS) Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 2 Departamento de Química Orgánica e Instituto de Investigación Sanitaria Galicia Sur (IISGS), Universidade de Vigo, 36310 Vigo, Spain.
  • 3 Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 4 Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, 35131 Padova, Italy.
  • 5 Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
  • 6 Departamento de Química Orgánica e Instituto de Investigación Sanitaria Galicia Sur (IISGS), Universidade de Vigo, 36310 Vigo, Spain. Electronic address: [email protected].
PMID: 32932120 DOI: 10.1016/j.bioorg.2020.104203
Abstract

The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC50 = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.

Keywords

Coumarin-pyridazine hybrids; In vivo study; MAO-B; Parkinson’s disease; SAR study.

Figures