A Multitarget Approach against Neuroinflammation: Alkyl Substituted Coumarins as Inhibitors of Enzymes Involved in Neurodegeneration
Emanuela Berrino,
Simone Carradori,
Fabrizio Carta,
Francesco Melfi,
Marialucia Gallorini,
Giulio Poli,
Tiziano Tuccinardi,
José G. Fernández-Bolaños,
Óscar López,
Jacobus P. Petzer,
Anél Petzer,
Paolo Guglielmi,
Daniela Secci,
Claudiu T. Supuran
Affiliations
Emanuela Berrino
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Simone Carradori
Department of Pharmacy, ‘‘G. d’Annunzio” University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
Fabrizio Carta
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Florence, Italy
Francesco Melfi
Department of Pharmacy, ‘‘G. d’Annunzio” University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
Marialucia Gallorini
Department of Pharmacy, ‘‘G. d’Annunzio” University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
Giulio Poli
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Tiziano Tuccinardi
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
José G. Fernández-Bolaños
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41012 Seville, Spain
Óscar López
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41012 Seville, Spain
Jacobus P. Petzer
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2531, South Africa
Anél Petzer
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2531, South Africa
Paolo Guglielmi
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Daniela Secci
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Claudiu T. Supuran
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Florence, Italy
Neurodegenerative disorders (NDs) include a large range of diseases characterized by neural dysfunction with a multifactorial etiology. The most common NDs are Alzheimer’s disease and Parkinson’s disease, in which cholinergic and dopaminergic systems are impaired, respectively. Despite different brain regions being affected, oxidative stress and inflammation were found to be common triggers in the pathogenesis and progression of both diseases. By taking advantage of a multi-target approach, in this work we explored alkyl substituted coumarins as neuroprotective agents, capable to reduce oxidative stress and inflammation by inhibiting enzymes involved in neurodegeneration, among which are Carbonic Anhydrases (CAs), Monoamine Oxidases (MAOs), and Cholinesterases (ChEs). The compounds were synthesized and profiled against the three targeted enzymes. The binding mode of the most promising compounds (7 and 9) within MAO-A and -B was analyzed through molecular modeling studies, providing and explanation for the different selectivities observed for the MAO isoforms. In vitro biological studies using LPS-stimulated rat astrocytes showed that some compounds were able to counteract the oxidative stress-induced neuroinflammation and hamper interleukin-6 secretion, confirming the success of this multitarget approach.
