A library of monosubstituted chalcones (1–17) bearing electron-donating and electron-withdrawing groups on both aromatic rings were selected. The cell viability on human tumor cell lines was evaluated first. The compounds unable to induce detectable cytotoxicity (1, 13, and 14) were tested using the monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B, acting as competitive inhibitors, with 13 and 14 showing the best profiles. In particular, 13 exhibited a potency higher than that of safinamide, taken as a reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similar to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-selective inhibitors for the treatment of neurodegenerative diseases.

Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase‑B / L.G. Iacovino, L. Pinzi, G. Facchetti, B. Bortolini, M.S. Christodoulou, C. Binda, G. Rastelli, I. Rimoldi, D. Passarella, M. Luisa Di Paolo, A. Lisa Dalla Via. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - (2021). [Epub ahead of print] [10.1021/acsmedchemlett.1c00238]

Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase‑B

G. Facchetti
Co-primo
;
M.S. Christodoulou;I.S. Rimoldi;D. Passarella;
2021

Abstract

A library of monosubstituted chalcones (1–17) bearing electron-donating and electron-withdrawing groups on both aromatic rings were selected. The cell viability on human tumor cell lines was evaluated first. The compounds unable to induce detectable cytotoxicity (1, 13, and 14) were tested using the monoamine oxidase (MAO) activity assay. Interestingly, they inhibit MAO-B, acting as competitive inhibitors, with 13 and 14 showing the best profiles. In particular, 13 exhibited a potency higher than that of safinamide, taken as a reference. Docking studies and crystallographic analysis showed that in human MAO-B 13 binds with the halogen-substituted aromatic ring in the entrance cavity, similar to safinamide, whereas 14 is accommodated in the opposite way. The main conclusion of this cell biology, biochemistry, and structural study is to highlights 13 as a chalcone derivative that is worth consideration for the development of novel MAO-B-selective inhibitors for the treatment of neurodegenerative diseases.
Chalcones; cytotoxicity; monoamine oxidase; molecular modeling; crystallographic analysis
Settore CHIM/03 - Chimica Generale e Inorganica
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/11 - Biologia Molecolare
14-giu-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/854673
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