Series of 1,3-disubstituted ureas and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues were shown to inhibit human soluble epoxide hydrolase (sEH) with inhibition potency ranging from 40 pM to 9.2 nM. The measured IC50 values for some molecules were below the accuracy limit of the existing in vitro assays. Such an increase in activity was achieved by minimal structural modifications to the molecules of known inhibitors, including 4-[trans-4-(1-adamantylcarbamoylamino)cyclohexyl]oxybenzoic acid. For the chlorinated homologue of the latter the sharp jump in inhibitory activity can be (according to molecular dynamics data) the result of interactions - Cl-pi interaction. Considering the extremely high inhibitory activity, acceptable solubility and partial blockage of metabolically sensitive centres in their structures, some compounds are of interest for further in vivo biotesting.

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are “medicinal” molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand–protein complexes largely depends on the “spacer effect.” The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand–protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues.

The reaction of 2-isocyanatophenyl acetate with adamantyl and phenyl-containing amines gave the corresponding acetamides. Intermediate 2-isocyanatophenol formed in the course of the reaction undergoes intramolecular cyclization to 2-benzoxazolinone. These reactions proceed only with amines possessing basicity (pKb > 3.80).

A series of 1,3-disubstituted ureas containing 1,3,5-trisubstituted pyrazole and (adamantan-1-yl)methyl fragments were synthesized in the reaction of 1-(isocyanatomethyl)adamantane with 3- or 4-aminopyrazoles under mild conditions in 67-92% yields. The inhibitory activity of the obtained compounds with respect to human soluble epoxide hydrolase (sEH) was 16.2-50.2 nmol/l, with solubility in water of 45-85 μmol/l.

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing imidazolidine-2,4,5-trione or pirimidine-2,4,6-trione has been synthesized. Inhibition potency of the described compounds ranges from 8.4 mu M to 0.4 nM. The tested compounds possess higher water solubility than their preceding ureas. Molecular docking indicates new bond between the triones and the active site of sEH that in part explain the observed potency of the new pharmacophores. While less potent than the corresponding ureas, the modifications of urea group reported herein yield compounds with higher water solubility, thus permitting easier formulation.

A series of soluble epoxide hydrolase (sEH) inhibitors containing 2-fluorophenyl fragment was developed. Inhibition potency of the described compounds ranges from 0.7 to 630.9 nM. 1-(Adamantan-1-ylmethyl)-3-(2-fluorophenyl) urea (3b, IC50 = 0.7 nM) and 1-(adamantan-2-yl)-3-(2-fluorophenyl) urea (3i, IC50 =1.0 nM) were found to be the most potent sEH inhibitors within the described series. Crystal results suggest that potency is probably enhanced by extra hydrogen bond between the fluorine atom and catalytic tyrosine residues.

A series of 3-(adamantan-1-ylalkyl)-2-(O,S,Se)hydantoins were synthesized in the reaction of (adamantan-1-ylalkyl)heteroallenes with glycine ethyl ester hydrochloride under mild conditions in 75–85% yields. A method was developed for the synthesis of novel adamantan-1-ylalkyl isoselenocyanates, precursors in the synthesis of adamantylated 2-selenohydantoins. For the first time, 3-(adamantan-1-yl)-2-(O,S)hydantoins were synthesized via the reaction of 2-(O,S)hydantoins with 1,3-dehydroadamantane in 1,4-dioxane heated to reflux for 1 h in 75–80% yields.

A series of 1,3-(adamantan-1(2)-yl)imidazolidine-2,4,5-triones and 1,1'-(alkane-1,n-diyl)bis[3-(adamantan-1-yl)imidazolidine-2,4,5-triones] was synthesized via cyclization of 1,3-bis[adamantan-1(2)-ylureas] and 1,1'-(alkyl-1,n-diyl)bis[3-(adamantan-1-yl)ureas] with oxalyl chloride under mild conditions with high yields. All synthesized compounds were tested in vitro as inhibitors of soluble human epoxide hydrolase. A number of compounds have high inhibitory activity (IC50 1.6–650 nM), which makes them promising inhibitors of soluble epoxide hydrolase.