Discovery of A Novel Series of Quinazoline–Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents
2024
Alexandru Șandor | Ionel Fizeșan | Ioana Ionuț | Gabriel Marc | Cristina Moldovan | Ilioara Oniga | Adrian Pîrnău | Laurian Vlase | Andreea-Elena Petru | Ioana Macasoi | Ovidiu Oniga
Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline–thiazole hybrids (<b>SA01–SA07</b>) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC<sub>50</sub> =1.83-4.24 µM) on HepG2 cells compared to <b>sorafenib</b> (IC<sub>50</sub> = 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 <b>sorafenib</b> 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 <b>SA05</b> as the hybrid forming the most stable complex with VEGFR2 compared to <b>sorafenib</b>. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (<b>SA01–SA05, SA07</b>) displayed superior anti-proliferative activity (IC<sub>50</sub> = 0.79–5.85 µM) compared to <b>sorafenib</b> (IC<sub>50</sub> = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, <b>SA04</b> and <b>SA05,</b> through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to <b>sorafenib</b>, led to the confirmation of the anti-angiogenic potential.
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