Abstract
A series of derivatives of the potent dual soluble epoxide hydrolase (sEH)/5-lipoxygenase-activating protein (FLAP) inhibitor diflapolin was designed, synthesized, and characterized by 1H NMR, 13C NMR, and elemental analysis. These novel compounds were biologically evaluated for their inhibitory activity against sEH and FLAP. Molecular modeling tools were applied to analyze structure–activity relationships (SAR) on both targets. Results show that even small modifications on the lead compound diflapolin markedly influence the inhibitory potential, especially on FLAP, suggesting very narrow SAR.
Highlights
A wide range of chronic pathologies is related to unresolved or misdirected inflammatory processes
Results show that even small modifications on the lead compound diflapolin markedly influence the inhibitory potential, especially on formation by targeting the 5-LO-activating protein (FLAP), suggesting very narrow structure− activity relationships (SAR)
Current research focuses on the development of designed multiple ligands (DMLs).[7,8]
Summary
Epoxyeicosatrienoic acids (EETs) toward the corresponding dihydroxyeicosatrienoic acids (DHETrEs).[3,12] In contrast to the anti-inflammatory EETs, DHETrEs possess less beneficial properties and are discussed to be rather related to inflammatory processes. Regarding inhibition of sEH, compounds with a 3-methyl moiety at the phenylene ring (subunit III) are most effective, and 2-methyl and unsubstituted phenylene lead to active compounds, and many of them are superior to diflapolin (13− 17, 19−21, 23, 26, 27) Notably, a chloro substituent in the ortho-position of the terminal phenyl reduces the inhibitory activity against sEH (12, 18, 24). In the sEH docking simulation, modifications in compound 13 (modified substitution on subunit V) and 21 (3-methyl on subunit III) did not affect the typical binding pattern between the urea moiety and the catalytic triad of sEH, that is, Asp 355, Tyr 466, and Tyr[383] (Figure 3). Our SAR study of novel diflapolin derivatives revealed important information regarding relevant substructures to target FLAP and sEH, respectively While both activities can be improved on one of the targets, it is challenging to modify the molecule and optimize both. Author Contributions The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript
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