2. Academic Validation
  3. Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors

Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors

  • Eur J Med Chem. 2023 Jul 5;255:115352. doi: 10.1016/j.ejmech.2023.115352.
Mariagrazia Rullo 1,  Gabriella La Spada 1,  Daniela Valeria Miniero 2,  Andrea Gottinger 3,  Marco Catto 1,  Pietro Delre 4,  Margherita Mastromarino 1,  Tiziana Latronico 2,  Sara Marchese 3,  Giuseppe Felice Mangiatordi 4,  Claudia Binda 3,  Anna Linusson 5,  Grazia Maria Liuzzi 2,  Leonardo Pisani 6
Affiliations

Affiliations

  • 1 Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy.
  • 2 Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70125, Bari, Italy.
  • 3 Dept. of Biology and Biotechnology, University of Pavia, via Ferrata 9, 27100, Pavia, Italy.
  • 4 CNR, Institute of Crystallography, 70126, Bari, Italy.
  • 5 Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
  • 6 Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
PMID: 37178666 DOI: 10.1016/j.ejmech.2023.115352
Abstract

Following a hybridization strategy, a series of 5-substituted-1H-indazoles were designed and evaluated in vitro as inhibitors of human Monoamine Oxidase (hMAO) A and B. Among structural modifications, the bioisostere-based introduction of 1,2,4-oxadiazole ring returned the most potent and selective human MAO B inhibitor (compound 20, IC50 = 52 nM, SI > 192). The most promising inhibitors were studied in cell-based neuroprotection models of SH-SY5Y and astrocytes line against H2O2. Moreover, preliminary drug-like features (aqueous solubility at pH 7.4; hydrolytic stability at acidic and neutral pH) were assessed for selected 1,2,4-oxadiazoles and compared to amide analogues through RP-HPLC methods. Molecular docking simulations highlighted the crucial role of molecular flexibility in providing a better shape complementarity for compound 20 within MAO B enzymatic cleft than rigid analogue 18. Enzymatic kinetics analysis along with thermal stability curves (Tm shift = +2.9 °C) provided clues of a tight-binding mechanism for hMAO B inhibition by 20.

Keywords

1,2,4-Oxadiazole; 1H-indazole; Bioisostere; Monoamine oxidases; Neuroprotection; Tight-binder.

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