Synthesis and Properties of 1,3-Disubstituted Ureas Containing (Adamantan-1-yl)(phenyl)methyl Fragment Based on One-Pot Direct Adamantane Moiety Inclusion.

A one-stage method for the preparation of 1-[isocyanato(phenyl)methyl]adamantane containing a phenylmethylene fragment located between the adamantane fragment and the isocyanate group, and 1-[isocyanato(phenyl)methyl]-3,5-dimethyladamantane with additional methyl groups at the nodal positions of adamantane, with a yield of 95% and 89%, respectively, is described. The method includes the direct inclusion of an adamantane moiety through the reaction of phenylacetic acid ethyl ester with 1,3-dehydroadamantane or 3,5-dimethyl-1,3-dehydroadamantane followed by the hydrolysis of the obtained esters. The reaction of 1-[isocyanato(phenyl)methyl]adamantane with fluorine(chlorine)-containing anilines gave a series of 1,3-disubstituted ureas with 25-85% yield. 1-[Isocyanato(phenyl)methyl]-3,5-dimethyladamantane was involved in the reactions with fluorine(chlorine)-containing anilines and trans-4-amino-(cyclohexyloxy)benzoic acid to obtain another series of ureas with a yield of 29-74%. The resulting 1,3-disubstituted ureas are promising inhibitors of the human soluble epoxide hydrolase (hsEH).

Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety.

The inhibitory potency of the series of inhibitors of the soluble epoxide hydrolase (sEH) based on the selenourea moiety and containing adamantane and aromatic lipophilic groups ranges from 34.3 nM to 1.2 µM. The most active compound 5d possesses aliphatic spacers between the selenourea group and lipophilic fragments. Synthesized compounds were tested against the LPS-induced activation of primary murine macrophages. The most prominent anti-inflammatory activity, defined as a suppression of nitric oxide synthesis by LPS-stimulated macrophages, was demonstrated for compounds 4a and 5b. The cytotoxicity of the obtained substances was studied using human neuroblastoma and fibroblast cell cultures. Using these cell assays, the cytotoxic concentration for 4a was 4.7-18.4 times higher than the effective anti-inflammatory concentration. The genotoxicity and the ability to induce oxidative stress was studied using bacterial lux-biosensors. Substance 4a does not exhibit genotoxic properties, but it can cause oxidative stress at concentrations above 50 µM. Put together, the data showed the efficacy and safety of compound 4a.

Ureas derived from camphor and fenchone reveal enantiomeric preference of human soluble epoxide hydrolase.

The soluble epoxide hydrolase (sEH) is a potential target to treat cardiovascular, renal and neuronal diseases. A series of sEH inhibitors containing naturally occurring lipophilic groups (originating from camphor and fenchone) were developed. Inhibitory potency ranging from 0.7 nM to 6.47 µM was obtained. It was discovered that ureas derived from L-camphor were more active against sEH (2.3-fold average) than the corresponding analogues derived from D-camphor indicating enantiomeric preference of sEH. Ureas derived from fenchone possess lower activity against sEH (ca. 80-fold on average) than their camphor-derived analogs due to the specific structure of the lipophilic fragment and show less enantiomeric preference (1.75-fold on average). Moreover, fenchone-derived ureas show no consistency in enantiomeric preference. Endo/exo-form of compound L-3a derived from L-camphor is 4-fold more potent than the corresponding analogue prepared from D-camphor (IC50 = 0.7 nM vs. 2.8 nM) making it the most promising sEH inhibitor among the tested series.