Dual VEGFR-2 and EGFR inhibitors of phenyldiazenes: anticancer evaluations, ADMET, docking, design and synthesis.

AIM

New phenyldiazene scaffold-linked heterocyclic pyrazole, pyrimidinone, pyrimidinthione, and/or triazine rings have been developed and synthesized.

METHODS & RESULTS: Cytotoxicity of our derivatives was estimated on four cancer and VERO normal cell lines targeting EGFR (epidermal growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) enzymes. Our new derivatives selectively inhibited both VEGFR-2 and EGFR as they have the essential structural requirements for inhibitors of both receptors. Derivative was the most active on A549, HCT116, HepG2, and MCF-7 cancers with half-maximal inhibitory concentration (IC) = 5.50, 9.77, 7.12, and 7.85 µM respectively. The assessed derivatives , , and showed IC = 54.40-62.60 μM against normal VERO (normal kidney) cells with low toxicity. In addition, derivatives and were discovered to be very good active inhibitors of VEGFR-2 at IC values of 1.15, 1.35, 140, 1.78 and 1.90 µM, respectively. Furthermore, derivatives and strongly repressed EGFR with IC = 0.28, 0.33, 0.35, and 0.50 µM correspondingly. Additionally, the highly active compounds and showed good ADMET profile.

CONCLUSION

Our derivatives could be considered as anticancer agents with dual VEGFR-2 and EGFR inhibition.