期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 20, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.115053
关键词
1-Arylpyrrolizin-3-ones; Substituted pyrroles; Anti-inflammatory activity; Licofelone; Ketorolac; TPA induced ear edema model
资金
- Secretaria de Investigacion y Posgrado (SIP)-IPN [20160791, 20170902, 20181332, 20180198, 20181966, 20195228, 20195287]
- CONACYT [178319, 282033, A1-S-17131]
- SIP-IPN (PIFI)
Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 19b-c/20b-c, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five-or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 19a-c/20a-c is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action.
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