Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Abstract

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea‐based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide‐based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P2) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P1) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12‐(3‐adamantan‐1‐yl‐ureido)dodecanoic acid as the reference standard. Compound 12e with a 4‐methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC50 value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.

Synthesis, Docking Study and Biological Evaluation of Amide‐Based Soluble Epoxide Hydrolase Inhibitors with Novel Secondary Pharmacophore of Pyrimidin‐2‐ol

“…In these compounds, two pharmacophores of amide and pyrimidin-2-ol ring were linked by a phenylene ring, and a para-substituted phenyl ring was considered the second linker-third pharmacophore (L 2 P 3 ) (Figure 2). [11,[18][19][20][21] Additionally, molecular docking analysis was performed based on the results from our previous published article [22] to reveal the significant interactions between the key pharmacophores of the synthesized compounds and active residues in terms of binding affinities. In our previous study, an extensive in silico study was performed to investigate the binding affinities of the newly synthesized quinazoline-4(3H)-one and 4,6-disubstituted pyridin-2(1H)-one derivatives against sEH enzyme.…”

Catalytic Generation of Remote C–N Axial Chirality through Atroposelectivede novoArene Construction

“…Nonetheless, the presence of the nitro group provides a handle for the introduction of other functionalities on this aryl ring through its reduction to amine (e.g., 5, Scheme 5) with SnCl 2 . 18 For example, the aniline derivative itself was isolated as the corresponding acetamide 6. Diazotization of amine 5 with NaNO 2 and camphor sulfonic acid (CSA) followed by treatment of the in situ generated diazonium salt with KI in acetic acid resulted in the iodo derivative 7.…”

“…Nonetheless, the presence of the nitro group provides a handle for the introduction of other functionalities on this aryl ring through its reduction to amine (e.g., 5 , Scheme ) with SnCl 2 . For example, the aniline derivative itself was isolated as the corresponding acetamide 6 .…”