title: Synthesis and biological evaluation of a new class of benzothiazines as neuroprotective agents.
abstract: Neurodegenerative diseases are disorders related to the degeneration of central neurons that gradually lead to various, severe alterations of cognitive and/or motor functions. Currently, for no such diseases does any pharmacological treatment exist able to arrest its progression. Riluzole (1) is a small molecule able to interfere with multiple cellular and molecular mechanisms of neurodegeneration, and is the only approved treatment of amyotrophic lateral sclerosis (ALS), the progression of which proved to significantly slow, thus increasing somewhat average survival. Here we report the synthesis of differently functionalized 4H-3,1-benzothiazine (5-6) and 2H-1,4-benzothiazine (7) series as superior homologues of 1. Biological evaluation demonstrated that amidine 4H-3,1-benzothiazine derivatives 5b-d can reduce glutamate and LDH release in the oxygen/glucose deprivation and reperfusion model (OGD/R) applied to brain slices with a higher potency than 1. Moreover the mentioned compounds significantly reduce glutamate- and 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in neuroblastoma cells. In addition, the same compounds limit ROS formation in both neuronal preparations. Finally, 5c proved effective in inhibiting neuronal voltage-dependent Na+and Ca2+-channels, showing a profile comparable with that of 1.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Chelini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy; Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Capua
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Fisiologia Generale, Università di Pavia, Via Forlanini 6, 27100 Pavia, Italy.
authors.forename: Loretta
authors.initials: L
authors.lastname: Castelli
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ricci
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Erminia
authors.initials: E
authors.lastname: Leonelli
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.affiliation: Rottapharm Biotech, Via Valosa di Sopra 7, 20052 Monza, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Fisiologia Generale, Università di Pavia, Via Forlanini 6, 27100 Pavia, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Magistretti
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Via A. Moro, 53100 Siena, Italy. Electronic address: maurizio.anzini@unisi.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D015220:Calcium Channels / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D018698:Glutamic Acid / Q000172:deficiency; D006801:Humans; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species; D013843:Thiazines / Q000138:chemical synthesis / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects
chemical_list: C446962:1,4-benzothiazine; D015220:Calcium Channels; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013843:Thiazines; D061566:Voltage-Gated Sodium Channels; D018698:Glutamic Acid; D010100:Oxygen
keywords: Benzothiazine derivatives; Neurodegenerative diseases; Neuronal voltage-dependent Na(+) and Ca(2+) currents; Neuroprotective agents; SH-SY5Y cells