New isoxazolidinone and 3,4-dehydro-β-proline derivatives as antibacterial agents and MAO-inhibitors: A complex balance between two activities.
Among the different classes of antibiotics, oxazolidinone derivatives represent important drugs, since their unique mechanism of action overcomes commonly diffused multidrug-resistant bacteria. Anyway, the structural similarity of these molecules to monoamino oxidase (MAO) inhibitors, like toloxatone and blefoxatone, induces in many cases loss of selectivity as a major concern. A small library of compounds based on isoxazolidinone and dehydro-β-proline scaffold was designed with the aim to obtain antibacterial agents, evaluating at the same time the potential effects of structural features on MAO inhibitory behaviour. The structural modification introduced in the backbone, starting from Linezolid model, lead to a significant loss in antibiotic activity, while a promising inhibitory effect could be observed on monoamino oxidases. These interesting results are also in agreement with docking experiments suggesting a good binding pose of the synthesized compounds into the pocket of the oxidase enzymes, in particular of MAO-B.
Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
Lucia
L
Ferrazzano
Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
Angelo
A
Viola
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
Elena
E
Lonati
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
Alessandra
A
Bulbarelli
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
Rosario
R
Musumeci
Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy.
Clementina
C
Cocuzza
Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy.
Marco
M
Lombardo
Department of Chemistry, University of Bologna, Via Selmi 2, 40126, Bologna, Italy. Electronic address: alessandra.tolomelli@unibo.it.
Alessandra
A
Tolomelli
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D013293:Enterococcus faecalis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D008996:Monoamine Oxidase Inhibitors; D011392:Proline; D008995:Monoamine Oxidase; C072401:beta-proline
3,4-Dehydro-beta-proline; Antibiotic; Isoxazolidinone; Linezolid; Monoamino oxidase