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

• Novel 2-chloro-4-anilino-quinazolines as EGFR and VEGFR-2 dual inhibitors.
• Structure–activity relationship for EGFR and VEGFR-2 inhibition.
• Docking studies lead to identification of pharmacophoric groups for both kinases.
• H-Bond donor group at para position of the aniline moiety is important for inhibition.

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.

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