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Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors

2013; Elsevier BV; Volume: 71; Linguagem: Inglês

10.1016/j.ejmech.2013.10.058

1768-3254

Maria Letícia de Castro Barbosa, Lı́dia Moreira Lima, Roberta Tesch, Carlos Maurício R. Sant’Anna, Frank Totzke, Michael H.G. Kubbutat, Christoph Schächtele, Stefan Laufer, Eliezer J. Barreiro,

Synthesis of Tetrazole Derivatives

Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites.