Discovery two potent and new inhibitors of 15-lipoxygenase: (E)-3-((3,4-dihydroxybenzylidene) amino)-7-hydroxy-2H-chromen-2-one and (E)-O-(4-(((7-hydroxy-2-oxo-2H-chromen-3-yl) imino)methine) phenyl)dimethylcarbamothioate

Núñez, Carolina; Morales, Nicole; García‐Beltrán, Olimpo; Mascayano, Carolina; Fierro, Angélica

doi:10.1007/s00044-017-1968-9

Cited by 4 publications

(1 citation statement)

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“…Since 2011, this structure is largely used for the molecular modeling of potential 5‐LO inhibitors. Considered as a valid surrogate for 12‐ and 15‐LO as reported previously (Nuñez et al, 2017; Tsolaki et al, 2018), soybean lipoxygenase‐3 (1N8Q) was used for the molecular docking of our best inhibitors of the biosynthesis of 12‐ and 15‐LO products. The lack of a complete structure of the human 12‐LO and 15‐LO justifies this choice.…”

Section: Resultsmentioning

confidence: 99%

Single and multiple inhibitors of the biosynthesis of 5‐, 12‐, 15‐lipoxygenase products derived from cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate: Synthesis and structure–activity relationship

Touaibia,

Chiasson,

Robichaud

et al. 2024

Drug Development Research

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The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure–activity study was carried out, which led to the discovery of several novel compounds (16a‐c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5‐, 12‐ and 15‐LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA‐approved 5‐LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α‐position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12‐ and 15‐LO products. Compounds 16a, 17a far surpassed baicalein, a known 12‐LO inhibitor, as inhibitors of 12‐LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α‐position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15‐LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5‐LO active site.

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Section: Resultsmentioning

confidence: 99%