Grady R W, Bienen E J, Clarkson A B
Mol Biochem Parasitol. 1986 Oct;21(1):55-63. doi: 10.1016/0166-6851(86)90079-4.
Alkyl esters of 3,4-dihydroxybenzoic acid are inhibitors of the sn-glycerol-3-phosphate oxidase system of Trypanosoma brucei brucei in vitro and have significant trypanocidal activity in vivo when combined with glycerol. While the parent acid has little inhibitory activity in vitro, the esters are highly active with activity increasing as the chain length of the esterifying alcohol increases. The n-dodecyl ester was more than 400 times as active as salicylhydroxamic acid and 15 times more active than the corresponding p-n-alkyloxybenzhydroxamic acid, one of the most active sn-glycerol-3-phosphate oxidase inhibitors previously reported. When combined with glycerol (to block an alternative pathway of glycolysis) and tested in vitro against intact parasites, this ester was 100 times more effective than salicylhydroxamic acid and 10 times more effective than p-n-dodecyloxybenzhydroxamic acid. It was also active against T. b. brucei in mice when combined with glycerol whereas the latter compound was not. Esters of 3,4,5-trihydroxybenzoic acid (gallic acid) were also highly active while those of 2,3-dihydroxybenzoic acid were much less inhibitory and those of 2,5-dihydroxybenzoic acid were inactive. A related compound, 2',4',5'-trihydroxybutyrophenone, was also active as predicted by its structure but was too toxic to be of interest as a drug candidate.
3,4-二羟基苯甲酸的烷基酯在体外是布氏布氏锥虫sn-甘油-3-磷酸氧化酶系统的抑制剂，与甘油联合使用时在体内具有显著的杀锥虫活性。虽然母体酸在体外几乎没有抑制活性，但这些酯具有高活性，且随着酯化醇链长度的增加活性增强。正十二烷基酯的活性比水杨羟肟酸高400多倍，比相应的对正烷氧基苯甲羟肟酸（先前报道的最具活性的sn-甘油-3-磷酸氧化酶抑制剂之一）高15倍。当与甘油联合使用（以阻断糖酵解的替代途径）并在体外针对完整寄生虫进行测试时，该酯比水杨羟肟酸有效100倍，比对正十二烷氧基苯甲羟肟酸有效10倍。当与甘油联合使用时，它对小鼠体内的布氏布氏锥虫也有活性，而后者则没有。3,4,5-三羟基苯甲酸（没食子酸）的酯也具有高活性，而2,3-二羟基苯甲酸的酯抑制作用小得多，2,5-二羟基苯甲酸的酯则无活性。一种相关化合物2',4',5'-三羟基丁酰苯也如结构预测的那样具有活性，但毒性太大，无法作为候选药物。
