伯喹衍生物溶血毒性的构效关系研究

STUDY ON STRUCTURE-ACTIVITY RELATIONSHIPS OF HEMOLYTIC TOX1CITY OF PRIMAQUINE DERIVATIVES

以结合肝微粒体代谢的抗疟药溶血毒性体外检测法测试伯喹(PQ)及其13个衍生物的溶血能力,并以直接体外法测定6个推测的PQ代谢产物的溶血毒性。结果表明,在PQ衍生物中,4-甲基PQ溶血毒性低于PQ,5-三氟乙酰基PQ溶血毒性与PQ相似,而8-伯氨基侧链改变对PQ溶血毒性无明显影响。在推测的PQ代谢产物中,5-OH PQ与5,6-OH PQ的溶血毒性远强于PQ,6-OH PQ、AQD与AQL的溶血毒性也比PQ强,唯独MAQ无明显溶血毒性。

Primaquine (PQ) and it's 13 derivatives were tested in an in vitro assay system incor-; porated with liver-microsomal metabolism for their hemolytic toxicity, and 6 putative meta-; bolites of PQ were also assayed in the same system without microsomal metabolism. The results showed that in the 13 derivatives, the hemolytic toxicity of 4-methyl PQ derivatives was lower than that of PQ while 5-trifluoroacetyl PQ derivatives exhibited similar hemolytic potential to PQ. Various modification of the 8-amino side chain of PQ has no significant effect on the hemolytic toxicity of PQ. In the 6 putative metabolites of PQ, 5-OH PQ and 5,6-OH PQ were the most potent hemolytic toxidants which could produce similar level of methemoglobin formation at concentrations several orders of magnitude less than that of PQ, while the hemolytic toxicity of 6-OH PQ, AQD and AQL was also higher than that of PQ itself. MAQ was the only one which exhibited no hemolytic toxicity.