LAUSR

The present study aimed to design and synthesize a series of 2‐hydroxy‐3‐(4‐aryl‐1‐piperazinyl)propyl phthalimide derivatives, which are analogs of 1H‐pyrrolo[3,4‐c]pyridine‐1,3(2H)‐dione derivatives with proven analgesic effect. In accordance with the basic principle proposed by Lipinski's rule, the probable bioavailabilities of the F1–F4 phthalimides were assessed. The obtained values indicate good absorption after oral administration and the ability to cross the blood–brain barrier. The four compounds F1–F4 differing in the type of pharmacophore in the phenyl group of the 2‐hydroxy‐3‐(4‐aryl‐1‐piperazinyl)propyl on the imide nitrogen atom (R, F1–F3) and the 4‐benzhydryl analog (F4) were selected for in vitro and in vivo studies. Based on the in vitro studies, the effects of compounds F1–F4 on cell viability/proliferation and COX‐2 levels were evaluated. Moreover, using in vivo methods, the compounds were tested for antinociceptive activity in models of acute pain (the writhing and the hot‐plate tests) in mice. Their influence on the motor coordination effect and locomotor activity was also tested. The obtained results revealed that the compounds F1–F4 strongly suppress the pain of peripheral origin and to a lesser extent (F1–F3) pain of central/supraspinal origin. In the in vitro studies, F1–F4 reduced the COX‐2 level in lipopolysaccharide‐activated RAW 264.7 cells, which suggests their anti‐inflammatory activity.