Discovery of new 1-aryl-3-phenylureas as promising PDGFRa and VEGFR-2 inhibitors and apoptosis inducers.

Targeted medicines can halt the growth and the development of tumors by blocking specific molecular targets linked to cancer. PDGFR and VEGFR-2 are distinguished by their critical roles in angiogenesis and oncogenesis. A new library of 1-aryl-3-phenylureas, 4-15 were designed and created as PDGFR and VEGFR-2 inhibitors. Three potent compounds, 4, 5, and 7, were chosen for the five-dose test after the NCI-Bethesda USA assessed their anticancer activity; their respective full GI50s were 9.3, 5.92, and 6.18 μM. More precisely, compound 7 demonstrated moderate selectivity indices for colon cancer and leukemia (SI 4.57, 3.04) respectively, with a remarkable safety ratio (SR VERO: 103.3, WI-38: 72.24) against leukemia. Afterwards, they were tested for PDGFRa and VEGFR-2 inhibitory potential. The PDGFRa assay results showed that compound 4 (IC50 0.617μM) outperformed the reference drug, imatinib (IC50 0.925μM), while 7 (IC50 1.1μM) was on par with imatinib. Compared to sorafenib, they were less effective as VEGFR2 inhibitiors. Remarkably, compound 7 is a simultaneously suppresses the pERK1/2 and pAKT pathways with approximately 0.3 fold inhibition compared to control. Furthermore, 7 reduced the antiapoptotic gene Bcl2 while inducing apoptotic effect by upregulating key apoptotic genes such BAX, P53, and caspase 3. Molecular docking further supported the mechanism showing the affinity of target compounds for PDGFRa and VEGFR-2 active site. According to ADME prediction, most of our library had zero violations of the Lipinski and Veber parameters with no BBB penetration, suggesting that these derivatives have intriguing drug-like qualities with few adverse effects.