Design,synthesis, and evaluation of the anticonvulsant and antidepressant activities of pyrido[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidine derivatives

A series of pyrido2,3-d]pyrimidine derivatives (4a–4n, 5a–5n, 6, and 7) were designed and synthesized as potential anticonvulsants and antidepressants. Their pharmacological activities were evaluated by maximal electroshock test, forced swimming test, and tail suspension test in mice. Pharmacological analyses showed that compounds 4-benzyl-6,8-dimethylpyrido3,2-e]tetrazolo1,5-a]pyrimidin-5(4H)-one (4a) and 4-(3-fluorobenzyl)-6,8-dimethylpyrido3,2-e]tetrazolo1,5-a]pyrimidin-5(4H)-one (4e) exhibited the greatest anticonvulsant activity (PI 12.02 and 12.25, respectively, 30 min after intraperitoneal injection), and were more efficient than the reference drug, carbamazepine. In addition, 4-(4-fluorobenzyl)-6,8-dimethylpyrido3,2-e]tetrazolo1,5-a]pyrimidin-5(4H)-one (4f) and 6-(4-fluorobenzyl)-2,4-dimethylpyrido3,2-e]1,2,4]triazolo4,3-a]pyrimidin-5(6H)-one (5f) possessed potent antidepressant properties that lead to significant reduction in the duration of the immobility time than did the control (P < 0.001), which possessed activities similar to those of fluoxetine. 4f showed obvious antidepressant activity at doses of 10 mg/kg.