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Bioisosteric replac...
Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors
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- Rullo, Mariagrazia (författare)
- Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy
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- La Spada, Gabriella (författare)
- Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy
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- Miniero, Daniela Valeria (författare)
- Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, Bari, Italy
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- Gottinger, Andrea (författare)
- Dept. of Biology and Biotechnology, University of Pavia, via Ferrata 9, Pavia, Italy
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- Catto, Marco (författare)
- Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy
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- Delre, Pietro (författare)
- CNR, Institute of Crystallography, Bari, Italy
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- Mastromarino, Margherita (författare)
- Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy
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- Latronico, Tiziana (författare)
- Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, Bari, Italy
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- Marchese, Sara (författare)
- Dept. of Biology and Biotechnology, University of Pavia, via Ferrata 9, Pavia, Italy
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- Mangiatordi, Giuseppe Felice (författare)
- CNR, Institute of Crystallography, Bari, Italy
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- Binda, Claudia (författare)
- Dept. of Biology and Biotechnology, University of Pavia, via Ferrata 9, Pavia, Italy
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- Linusson, Anna, 1970- (författare)
- Umeå universitet,Kemiska institutionen
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- Liuzzi, Grazia Maria (författare)
- Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, Bari, Italy
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- Pisani, Leonardo (författare)
- Dept. of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy
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Dept of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, Bari, Italy Dept. of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, Bari, Italy (creator_code:org_t)
- Elsevier, 2023
- 2023
- Engelska.
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 255
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- 1
- 2
- 4-Oxadiazole
- 1H-indazole
- Bioisostere
- Monoamine oxidases
- Neuroprotection
- Tight-binder
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Rullo, Mariagraz ...
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La Spada, Gabrie ...
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Miniero, Daniela ...
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Gottinger, Andre ...
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Catto, Marco
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Delre, Pietro
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visa fler...
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Mastromarino, Ma ...
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Latronico, Tizia ...
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Marchese, Sara
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Mangiatordi, Giu ...
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Binda, Claudia
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Linusson, Anna, ...
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Liuzzi, Grazia M ...
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Pisani, Leonardo
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