Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline-thiazole hybrids () as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC =1.83-4.24 µM) on HepG2 cells compared to (IC = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified as the hybrid forming the most stable complex with VEGFR2 compared to . The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds () displayed superior anti-proliferative activity (IC = 0.79-5.85 µM) compared to (IC = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, and through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to , led to the confirmation of the anti-angiogenic potential.