TY - JOUR
T1 - Synthesis and highly potent anti-inflammatory activity of licofelone- and ketorolac-based 1-arylpyrrolizin-3-ones
AU - Madrigal, Damian A.
AU - Escalante, Carlos H.
AU - Gutiérrez-Rebolledo, Gabriel A.
AU - Cristobal-Luna, José M.
AU - Gómez-García, Omar
AU - Hernández-Benitez, Roberto I.
AU - Esquivel-Campos, Ana L.
AU - Pérez-Gutiérrez, Salud
AU - Chamorro-Cevallos, Germán A.
AU - Delgado, Francisco
AU - Tamariz, Joaquín
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/10/15
Y1 - 2019/10/15
N2 - 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.
AB - 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.
KW - 1-Arylpyrrolizin-3-ones
KW - Anti-inflammatory activity
KW - Ketorolac
KW - Licofelone
KW - Substituted pyrroles
KW - TPA induced ear edema model
UR - http://www.scopus.com/inward/record.url?scp=85071322133&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2019.115053
DO - 10.1016/j.bmc.2019.115053
M3 - Artículo
C2 - 31471100
AN - SCOPUS:85071322133
SN - 0968-0896
VL - 27
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 20
M1 - 115053
ER -