Discovery of 6-Arylurea-2-arylbenzoxazole and 6-Arylurea- 2-arylbenzimidazole Derivatives as Angiogenesis Inhibitors:Design, Synpesis and in vitro Biological Evaluation

摘要

We embarked on astructuraloptimization campaign aimed at pe discoveryofnovel anti-angiogenesis agents wip previous- ly reported imidazole kinase inhibitors as alead compound. A library of 29 compounds was synpesized.Several title com- pounds exhibited selective inhibitory activities against vascular endopelial growp factor receptor 2(VEGFR-2) over epidermal growp factor receptor(EGFR) kinase;pese compounds also displayed selective and potent antiproliferative activity against pree cancercell lines. pe newly synpesized compounds were evaluated for anti-angiogenesis activity by chick chorioal- lantoic membrane(CAM) assay.Among pem, 1-(2-(2-chloro- phenyl)benzo[d]oxazol-5-yl)-3-(4-(trifluoromepoxy)phenyl)urea (compound 5n)showedpe most potent anti-angiogenesis ca- pacity,efficient cytotoxic activities (in vitro against humanum- bilical vein endopelial cells (HUVEC), H1975, A549, and HeLa cell lines, wip respectiveIC50 valuesof8.46, 1.40, 7.61, and 0.28 mm), and an acceptable level of VEGFR-2 kinase inhibition (IC50=0.25 mm). Molecular docking analysisrevealed 5n to be atype II inhibitor of VEGFR-2 kinase. In general, pese results indicatepat pese 6-arylurea-2-arylbenzoxazole/benzimidazole derivatives are promisinginhibitors of VEGFR-2 kinase for po- tentialdevelopment into anti-angiogenesis drugs.