Synthesis of New N,N'-Diarylureas and Their Theoretical Study as Cannabinoid-1 Receptor Inhibitors.

A series of new N,N'-diarylureas is reported as potential cannabinoid-1 (CB-1) receptor inhibitors. The synthesis of the new N,N'-diarylureas is achieved from the reaction of two substituted anilines with the aid of triphosgene. One aniline carries a pyrazol-1-yl or 1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl propan-2-one group at position-3, while the other aniline is substituted by fluoro, bromo, methoxy, cyano, morpholino, or 4-methyl-2-nitro groups. All new compounds are investigated through density functional theory calculations, molecular docking, and molecular dynamics simulations, showing a strong ability to bind to the orthosteric pocket of the CB-1 receptor and to the allosteric position when CB1 is in complex with agonist AM841. The binding is comparable to that of the well-known CB-1 inhibitor PSNBAM-1. Especially, 1-{3-[2-(1H-pyrazol-1-yl)acetyl]phenyl}-3-(4-methyl-3-nitrophenyl)urea presents better theoretical results than PSNBAM-1.