Papers of the Week

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.