A Novel Series of Thromboxane A_2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities

A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A_2(TXA_2)synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-{5-substituted-3-[2-(imidazol-1-yl)ethyl[indolin-1-yl}propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA_2-dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative(13)showed about 35-fold higher inhibitory activity on TXA_2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of α-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.