O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

Abstract

Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, O-allyl and O-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while O-geranyl and O-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC50 = 0.74 μM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC50 = 10.4 μM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.

Novel 3‐aryl‐5‐substituted‐coumarin analogues: Synthesis and bioactivity profile

“…Our latest research focuses on the design, synthesis, and bioactivity evaluation of a series of 3‐aryl coumarin analogues as well as a series of prenyloxy derivatives of the natural compound umbelliferone (e.g., auraptene) (Kavetsou et al, ; Roussaki et al, ; Roussaki et al, ). The promising results of these works in combination with the literature data (Dos Santos Nascimento et al, ; Ibrar, Shehzadi, Saeed, & Khan, ; Jabbari, Mousavian, Seyedi, Bakavoli, & Sadeghian, ), which reveal the role of the phenyl group at the prenylated coumarin's skeleton (Wiart, ), as well as the role of different substitutions on the phenyl group of an acetyloxy coumarin (Musa, Latinwo, Joseph, & Badisa, ), led us to design new series of coumarin analogues which combine the 3‐aryl substituent and acetyloxy‐/hydroxy‐ or geranyloxy moiety in order to investigate the effect of the presence of these groups on the biological activity (Scheme ).…”

Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study

“…This supports previous findings that the replacement of a phenyl group attached on the coumarin ring by a 2-pyridyl group or by a morpholinyl group decreased the inhibitory activity of 6- and 7-substituted coumarins against lipoxygenase [ 43 ]. Additionally, in the study of lipoxygenase inhibition by O -prenylated 3-carboxycoumarins, O -isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition, while O -geranyl and O -farnesyl derivatives demonstrated potent inhibitory activity [ 44 ].…”

A novel class of human 15‐LOX‐1 inhibitors based on 3‐hydroxycoumarin

“…Enzyme preparation was down according to the pervious method which had been reported by Jabbari et al …”

“…More than 1,300 derivatives of coumarins, possessing anti‐inflammatory and anticancer properties, have been isolated from green plants, fungi, and bacteria . Several natural and synthetic derivatives of hydroxycoumarins have been reported as inhibitors of the lipo‐oxygenase pathways . Most of them inhibit the lipo‐oxygenase activity using redox mechanism with their hydroxyl groups .…”