DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL IMIDAZOLIDINONE-THIAZOLE AMIDE HYBRIDS AS INHIBITORS OF HUMAN SOLUBLE EPOXIDE HYDROLASE

9th EFMC Young Medicinal Chemists' Symposium, Nice, Fransa, 8 - 09 Eylül 2022

Soluble epoxide hydrolase (sEH, Ephx2) catalyzes the metabolism of epoxyeicosatrienoic acids (EETs) to

dihydroxyeicosatrienoic acids (DHETs) produced by the cytochrome P450 branch of the arachidonic acid

pathway, which is present in numerous organs such as the liver, kidney, lung, heart, and brain. EETs are natural

anti-inflammatory eicosanoids that suppress cytokine-induced inflammatory responses. sEH x-ray crystal

structures indicate that three catalytic residues, i.e., Asp335, Tyr383, Tyr466 are located at the corner of an

L-shaped active pocket. The amide, urea and carbamate primer pharmacophores have been central components

in the design of potent sEH inhibitors since carbonyl and proton-donating NH groups in these functions form

strong H-bonds with these catalytic residues in the central catalytic domain. A major part of the enzymatic

pocket is hydrophobic, despite the fact that each side of the pocket (10 and 15 Å long) accommodates a range of

functional groups. Although a number of highly potent she inhibitors have been reported, highly lipophilic

nature of the compounds cause limitations for further development [1, 2].

Apart from central urea/amide structures, novel sEH inhibitors have been developed through investigation of the

secondary pharmacophore structures that are expected to increase the interaction with the side pocket amino

acids [3]. The presence of a polar secondary pharmacophore group, which offers key advantages for the

compounds in terms of increased activity, could also improve the physicochemical properties of the compounds.

Within the context of this presentation, a series of potential sEH inhibitors containing unique

imidazolidinone-thiazole amide central structure, were designed and their interactions with the active site were

investigated. Our molecular docking results show that, in addition to the H-bond interactions with the amide

group, additional interactions with Gln384 and Trp336 in the long and with His524 in the short pocket stand out

to contribute to the inhibitory potency of the compounds. Consequently, the core structure we developed seems

to be promising for further development of sEH inhibitors and the initial computational and biological results

will be presented herein.