Benzamides and benzamidines as specific inhibitors of epidermal growth factor receptor and v-Src protein tyrosine kinases

The benzamides 1 and the benzamidines 2 as well as the cyclic benzamidines 3 were designed and synthesized as the mimics of 4-anilinoquinazolines for an inhibitor of EGFR tyrosine kinase. The specific inhibitions of EGFR tyrosine kinase were observed in the benzamides 1c and 1d, and the benzamidine 2a, whereas the specific inhibitions of v-Src kinase were observed in the benzamide 1j and the benzamidine 2d at a 10 mug/mL concentration of compounds. The cyclic benzamidines 3a and 3b showed potent kinase inhibition of EGFR at a 1.0 mug/mL concentration. According to the docking simulation using the X-ray structure of EGFR kinase domain in complex with erlotimb, the LigScore2 scoring function value of erlotimb was calculated as 5.61, whereas that of the benzamide 1c was 5.05. In a similar manner, the LigScore2 value of the cyclic benzamidine 3a was calculated as 5.10. (C) 2004 Elsevier Ltd. All rights reserved.