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

Abstract

We embarked on as tructuralo ptimization campaign aimed at the discoveryo fn ovel anti-angiogenesis agents with previously reported imidazole kinase inhibitors as al ead compound. A library of 29 compounds was synthesized.S everal title compounds exhibited selective inhibitory activities against vascular endothelial growth factor receptor 2( VEGFR-2) over epidermal growth factor receptor( EGFR) kinase;t hese compounds also displayed selective and potent antiproliferative activity against three cancerc ell lines. The newly synthesized compounds were evaluated for anti-angiogenesis activity by chick chorioallantoic membrane( CAM) assay.A mong them, 1-(2-(2-chloro-phenyl)benzo[d]oxazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 5n)s howedt he most potent anti-angiogenesis capacity,e fficient cytotoxic activities (in vitro against humanu mbilical vein endothelial cells (HUVEC), H1975, A549, and HeLa cell lines, with respectiveI C 50 valueso f8 .46, 1.40, 7.61, and 0.28 mm), and an acceptable level of VEGFR-2 kinase inhibition (IC 50 = 0.25 mm). Molecular docking analysisr evealed 5n to be at ype II inhibitor of VEGFR-2 kinase. In general, these results indicatet hat these 6-arylurea-2-arylbenzoxazole/benzimidazole derivatives are promisingi nhibitors of VEGFR-2 kinase for potentiald evelopment into anti-angiogenesis drugs.

Design, Synthesis and Anticancer Activity of a New Series of N-aryl-N′-[4-(pyridin-2-ylmethoxy)benzyl]urea Derivatives

“…The IR spectra were measured using a Bruker Fourier number infrared spectrometer (Agilent Corporation, Santa Clara, CA, USA). 1 H-NMR, 13 C-NMR, ESI-MS and HRMS spectra of the target compounds are available in the Supplementary Material (Figures S1-S80).…”

“…Mass spectra were measured with an electrospray (ESI-MS) on an Agilent 1100 Series LC/MSD Trap (Agilent Corporation, Santa Clara, CA, USA). 1 H-NMR and 13 C-NMR spectra were recorded on Bruker NMR spectrophotometers (Karlsruhe, Germany) using DMSO-d 6 as the solvent. The IR spectra were measured using a Bruker Fourier number infrared spectrometer (Agilent Corporation, Santa Clara, CA, USA).…”

“…These kinds of structures are an excellent pharmacodynamic structure in drug molecules [11]. In many small-molecule targeted kinase inhibitors, urea and urea isosteres, including aminopyrimidine, have been used in drug structures, some of which showed really favorable anti-cancer activity (Figure 1) [12,13]. Among the currently clinically used multi-target kinase inhibitors, sorafenib and its derivative regorafenib with a diaryl urea structure were the prime representatives, because they had excellent inhibitory effects on a variety of solid tumors [14,15].…”

“…) 13. C NMR (101 MHz, DMSO-d 6 ) δ 161.82, 155.94, 155.46, 149.62, 148.02, 147.18, 141.80, 133.59, 130.11, 124.73 (q, J = 272.3 Hz), 124.25 (q, J = 277.4 Hz), 122.07, 121.62, 119.69, 117.68, 114.28, 114.06, 112.08, 108.02 (d, J = 4.4 Hz), 71.56, 65.10 (q, J = 34.…”

“…) 13. C NMR (101 MHz, DMSO-d 6 ) δ 161.80, 155.96, 155.86, 154.40, 149.57, 148.05, 147.08, 134.08, 133.97, 124.28 (d, J = 277.9 Hz), 122.05, 119.91, 119.64, 114.33, 114.27, 112.06, 108.07, 71.58, 65.08 (q, J = 34.5 Hz), 55.99, 55.59, 43.09, 10.36; IR: 3312, 2940, 2839, 1631, 1571, 1508, 1467, 1417, 1376, 1363, 1308, 1271, 1241, 1160, 1136, 1030, 973, 862, 827, 669, 578, 524, 423; HRMS: 504.175179 ([M − H] − ) for C 25 H 25 F 3 N 3 O 5 , 506.189732 ([M + H] + ) for C 25 H 27…”