Synthesis of 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione, a novel hydrogen sulfide-releasing phthalimide hybrid, and evaluation of its activity in models of inflammatory pain

Abstract

Hydrogen sulfide (H₂S) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both H₂S donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel H₂S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-H₂S), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-H₂S (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-H₂S (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-H₂S (25 mg/kg, i.p.) was more sustained than that induced by the H₂S donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-H₂S antiallodynic activity. In conclusion, we synthesized a novel H₂S-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-H₂S activity may be due to H₂S release and activation of ATP-sensitive potassium channels. The demonstration of PTD-H₂S activity in models of pain stimulates further studies aiming to evaluate H₂S-releasing phthalimide hybrids as candidates for analgesic drugs.

Keywords: H(2)S; Hydrogen sulfide; Inflammation; Pain; Phthalimide analogue.