Synthesis and biological evaluation of amidine, guanidine, and thiourea derivatives of 2-amino(6-trifluoromethoxy)benzothiazole as neuroprotective agents potentially useful in brain diseases.
A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole termed 2, 3, and 4, respectively, and structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2a-e, 3a-f, and 4a,b was preliminarily tested by means of an in vitro protocol of ischemia/reperfusion injury. The results demonstrated that 2c and 3a-d significantly attenuated neuronal injury. Selected for testing of their antioxidant properties, compounds 3a-d were shown to be endowed with a direct ROS scavenging activity. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na(+) and Ca(2+) currents in neurons from rat piriform cortex. At 50 microM, compound 3b inhibited the transient Na(+) current to a much smaller extent than riluzole, whereas 3d was almost completely ineffective.
Anzini
Maurizio
M
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università di Siena, Via A. Moro, 53100 Siena, Italy. anzini@unisi.it
Chelini
Alessia
A
Mancini
Alessandra
A
Cappelli
Andrea
A
Frosini
Maria
M
Ricci
Lorenzo
L
Valoti
Massimo
M
Magistretti
Jacopo
J
Castelli
Loretta
L
Giordani
Antonio
A
Makovec
Francesco
F
Vomero
Salvatore
S
D000578:Amidines / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001927:Brain Diseases / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry; D017136:Ion Transport / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry
D000578:Amidines; D000975:Antioxidants; D052160:Benzothiazoles; D006146:Guanidines; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012964:Sodium; C005465:benzothiazole; D013890:Thiourea; D002118:Calcium