Synthesis of 4-alkoxy-2-phenylquinoline derivatives as potent antiplatelet agents

In our continuing search for novel antiplatelet agents, 4-alkoxy derivatives of 2-phenylquinoline as well as related compounds were prepared. Through biological screening, a preliminary structure–antiplatelet activity relationship was established. Compounds 5-ethyl-4-methoxy-2-phenylquinoline (8), 4-ethoxy-5-ethyl-2-phenylquinoline (9), 4-ethoxycarbonylmethoxy-5-ethyl-2-phenylquinoline (10), 4-ethoxycarbonylbutoxy-5-ethyl-2-phenylquinoline (12) and 5-ethyl-4-(N-ethylcarboxido)methoxy-2-phenylquinoline (17) all demonstrated potent antiplatelet activity. Among them, compound 8 was the most potent with an IC50 value of 0.08 μM and was about 3-fold more active than indomethacin. The mechanism of antiplatelet action of 8 is possibly through its inhibition on cyclooxygenase or thromboxane synthetase.