Design, synthesis and evaluation of the biological activity of novel coumarin derivatives

Coumarins, (2H-1-benzopiran-2-one) derivatives that can be isolated from several plants, have been reported for their anticoagulant, antimicrobial, anti-inflammatory or anticancer activity. Some of these structures are currently approved for the treatment of cardiovascular diseases (warfarin), as antibiotics (novobiocin or chlorobiocin) or as an anticancer drug (geiparvarin). Given the great potential of this structure and the limited number of studies that focus on molecules that derive from the 8th carbon of the benzopiranone heterocycle, we synthesized in this project thirty eight coumarin derivatives (2 - 50), twenty two of them being novel, by substituting to the 8th carbon of the benzopiran ring some aromatic and aliphatically subtituted piperidine and piperazines. Synthesized derivatives were evaluated for their anti-inflammatory activity, analgesic activity and cytotoxicity. Targeted molecules were synthesized in two steps. The first step consisted on the synthesis of the 7-hydroxy-4-methyl-chromen-2-one coumarin scaffold via the Pechmann reaction. In the second step, the 7-hydroxy-4-methyl-chromen-2-one coumarin scaffold, (compound 1), was derivatized with aromatic and aliphatic substituted piperazine and piperidine groups. Structures of synthesized compounds were elucidated with 1H-NMR, 13C-NMR, LC-MS, FT-IR. The anti-inflammatory and analgesic activities and cytotoxicity were performed in vitro. Cytotoxicity assays were carried out with the MTT test on RAW264.7 macrophage and MCF-7 breast cancer cells. The nitrite inhibition test was applied for evaluating the anti-inflammatory activity on RAW264.7 macrophage cells. Indomethacin (IND) and L-NAME were used as reference drugs for both anti-inflammatory and cytotoxicity tests. For the analgesic activity, PGE2 production was monitored. According to the results, compound 11, 23 and 31 revealed promising anti-inflammatory activity. Their results were better than the reference drugs and compound 11 was three times more active than IND. Additionally, compound 11 demonstrated some analgesic activity with low cytotoxicity. Keywords: Coumarin, piperazine, piperidine, anti-inflammatory activity, analgesic activity, cytotoxicity.