College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198-6125, United States.
Department of Pathology & Microbiology, College of Medicine, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, Nebraska 68198-5900, United States.
ACS Infect Dis. 2021 Jun 11;7(6):1578-1583. doi: 10.1021/acsinfecdis.1c00135. Epub 2021 May 10.
We now describe the physicochemical profiling, ADME, and antiparasitic activity of eight ,-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no ,-diarylurea had submicromolar potency against , two had submicromolar potencies against and , and five had submicromolar potencies against . appeared to be the most susceptible to growth inhibition by this compound series. Most of the ,-diarylureas had antiprotozoal selectivities ≥10. One ,-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.
我们现在描述了八种二芳基脲的物理化学特性、ADME 和抗寄生虫活性，以评估它们作为广谱抗原生动物化学型的潜力。色谱 LogD 值范围为 2.5 至 4.5；动力学水溶解度均≤6.3μg/mL，血浆蛋白结合率为 95%至 99%。所有化合物在人肝微粒体中的固有清除率均较低，但在小鼠肝微粒体中则没有。虽然没有二芳基脲对具有亚微摩尔的效力，但有两种对和具有亚微摩尔的效力，有五种对具有亚微摩尔的效力。似乎对该化合物系列的生长抑制最为敏感。大多数二芳基脲具有≥10 的抗原生动物选择性。有一种二芳基脲在疟疾和弓形体病的小鼠模型中具有明显的活性。
