Synthesis and pharmacological evaluation of aminoacetylenic isoindoline-1,3-dione derivatives as anti-inflammatory agents

Aminoacetylenic isoindoline-1,3-dione derivatives were synthesized from the reaction of potassium phthalimide with propargyl bromide to generate 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (ZM1). Treatment of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione with appropriate cyclic amines through Mannich reaction yielded five desired aminoacetylenic isoindoline-1,3-diones called, ZM2–ZM6. The IR, NMR and elemental analysis were consistent with the assigned structures. These synthetic compounds, except ZM6, produced significant (p < 0.05–0.01) dose-related inhibition of carrageenan-induced edema in rats following 3 and 5 h post-oral administration of 5, 10, and 20 mg/kg doses. The percent inhibition of edema varied between the compounds at 10 mg/kg dose being ZM3 > ZM5 > ZM4 > ZM2. These percent inhibitions for ZM3 and ZM5 were not significantly different than those of induced by Ibuprofen, Diclofenac and Celecoxib. At 20 mg/kg dose, ZM4 produced a statistically significant reduction of inflammation (p < 0.01) 1 h following administration and persisted for 5 h. Furthermore, all the compounds showed inhibition of COX-1 and COX-2 with maximum inhibition at 5 μM. However, the inhibition values were less than Diclofenac and Celecoxib. The best response was by ZM4 for COX-2 inhibition ranging from 28%, 91%, and 44%, for 2, 5, and 10 μM, respectively. Other ZM compounds such as ZM2, ZM3, and ZM5 exhibited inhibitory responses for COX-2 more than COX-1 at 5 μM. These results indicate that these ZM compounds have the potential to become anti-inflammatory drugs following further pharmacological and toxicological evaluations.