Synthesis and properties of 1-(3,5,7-trifluoroadamantan-1-yl)-3-R-ureas

A method comprising the use of a fluorinating agent, the Ishikawa’s reagent, at one of its steps was developed for the synthesis of 1,3,5-trifluoroadamantane-7-isocyanate from 3,5,7-trifluoroadamantane-1-carboxylic acid and diphenylphosphoryl azide. The reaction of 1,3,5-trifluoroadamantane-7-isocyanate with fluoroanilines gave 1,3-disubstituted ureas in the yields of 58–73%. The influence of number of the fluorine atoms in the adamantyl moiety on the melting point, lipophilicity, and water solubility of ureas was estimated, which allows one to intentionally tune these important properties of ureas as promising enzyme inhibitors. The molecular docking revealed the effectiveness of 4-({4-[3-(3,5,7-trifluoroadamantan-1-yl)ureido]cyclohexyl}oxy)benzoic acid in the inhibition of p38 MAPK, c-Raf and hsEH.