Synthesis and biological evaluation of amidine, guanidine, and thiourea derivatives of 2-amino(6-trifluoromethoxy)benzothiazole as neuroprotective agents potentially useful in brain diseases.

The aim of the present study was to develop new compounds related to riluzole as possible neuroprotective agents, and to assess their ability to interfere with different steps of the biochemical pathways that lead to neuronal injury, thus preventing/reducing tissue damage. A series of amidinic, guanidinic, and thioureic derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole (series 2, 3, and 4, respectively)structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2c-e, 3a-e and 4a was preliminary tested by means of an in vitro protocol of ischemia/reperfusion injury. Results demonstrated that 2c and 3a-d significantly attenuated neuronal injury while the other derivatives were ineffective. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na+ and Ca2+ currents in neurons from rat piriform cortex. At 50 μM, 3b inhibited the transient Na+ current to a much lesser extent than riluzole, whereas 3d was almost completely ineffective. Both compounds reduced the amplitude of high-voltage-activated currents amplitude in a concentration-dependent manner, but in a concentration range (IC50 = 24.1 µM and 112.9 µM for 3d and 3b, respectively) substantially higher than that at which neuroprotective effects are observed. These results strongly suggest that the main mechanisms of 3b and 3d neuroprotective action do not involve voltage-gated Na+ and Ca2+ channels. Finally, compounds 3a, 3b, 3c and 3d showed also antioxidant properties, indicating that they are also endowed with a direct ROS-scavenging activity.