Synthesis and Antidepressant Activity of 4-Alkyl-5-Bromo-2,4-Dihydro-2-(Thietan-3-YL)-1,2,4-Triazol-3-Ones

A series of 4-alkyl-5-bromo-2,4-dihydro-2-(thietan-3-yl)-1,2,4-triazol-3-ones ( IIa - g ) were synthesized by reacting 5-bromo-2,4-dihydro-2-(thietan-3-yl)-1,2,4-triazol-3-one ( I ) with alkyl halides and dimethyl sulfate. The structures of the synthesized compounds were confirmed by IR, PMR, and 13 C NMR spectroscopic data. The antidepressant activity of the synthesized compounds in non-inbred male mice was investigated using tail-suspension and forced-swim tests. Compounds I and IIa,c , f,g after a single intraperitoneal injection produced antidepressant effects in screening tests and did not cause sedative and/or psychostimulatory effects in the open-field test. Compound I produced an antidepressant effect comparable to that of fluoxetine, had low toxicity (class IV toxicity), and was superior to fluoxetine in therapeutic index and strength of the antidepressant effect after a course of administration. The calculated physicochemical properties and toxic risks showed that all synthesized compounds complied fully with Lipinski’s rule of five. The calculated drug score and absence of predicted toxic risks for the most active compound I suggested that it was promising for creating a new pharmaceutical substance with antidepressant activity.