Amidino-Containing Schiff Base Copper(II) and Iron(III) Chelates as a Thrombin Inhibitor

Four series of Schiff base copper(II) and iron(III) chelates were synthesized from 4-formyl-3-hydroxybenz-amidine or 3-formyl-4-hydroxybenzamidine and various L- or D-amino acids. Their inhibitory activities for bovine α-thrombin (abbreviated as thrombin) were determined. The most potent thrombin inhibitor in this series is copper (II) chelate (1g') derived from 4-formyl-3-hydroxybenzamidine and D-Trp. Its K_i value, 2.7×10^<-8>_M, is comparable to that of Argatroban (MD-805), which is a clinically used compound. The iron (III) chelates derived from 4-formyl-3-hydroxybenzamidine and hydrophobic L-amino acids (Val, He, Leu, Phe, Trp, Met) also exhibited higher inhibitory potency. It appears that coordination geometry composed of metal ion, amidino group, amino acid side chain is well accommodated to the thrombin active site. From the K_i values of Schiff base metal chelates for thrombin, the structure-activity relationships between the chelates and active site of thrombin were discussed.