Tsemperlidou Eirini, Georgiou Nikitas, Tzeli Demeter, Karousis Nikolaos, Varvounis George
Laboratory of Organic Chemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens, 15784, Greece.
Chempluschem. 2025 Aug;90(8):e202500270. doi: 10.1002/cplu.202500270. Epub 2025 Jul 7.
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.
报道了一系列新型N，N'-二芳基脲作为潜在的大麻素-1（CB-1）受体抑制剂。新型N，N'-二芳基脲的合成是通过两种取代苯胺在三光气的辅助下反应实现的。一种苯胺在3位带有吡唑-1-基、1H-1,2,3-三唑基或2H-1,2,3-三唑基丙-2-酮基团，而另一种苯胺被氟、溴、甲氧基、氰基、吗啉基或4-甲基-2-硝基取代。所有新化合物均通过密度泛函理论计算、分子对接和分子动力学模拟进行研究，结果表明它们在CB1与激动剂AM841形成复合物时，具有与CB-1受体的正构口袋和变构位点结合的强大能力。其结合能力与著名的CB-1抑制剂PSNBAM-1相当。特别是，1-{3-[2-(1H-吡唑-1-基)乙酰基]苯基}-3-(4-甲基-3-硝基苯基)脲的理论结果比PSNBAM-1更好。
