McCracken R O, Lipkowitz K B
Department of Biology, Indiana University-Purdue University, Indianapolis 46205.
J Parasitol. 1990 Dec;76(6):853-64.
An investigation of the biochemical effects of an anthelmintic, tioxidazole (TIOX, methyl 6-[n-propoxy]benzothiazole-2-carbamate), on Hymenolepis diminuta in experimentally infected rats is reported. The chemotherapeutic actions of TIOX on H. diminuta in vivo were accompanied by marked changes in worm weight and chemical composition. Tapeworms recovered from rats that had received a therapeutically effective dose of TIOX 24 hr earlier were significantly smaller and contained much less glycogen (as a percentage of the wet weight) than worms from untreated controls. In TIOX-treated worms, protein concentrations rose at a rate sufficient to offset the decline in glycogen concentration. Glycogen/protein ratios in TIOX-treated worms were considerably lower than the corresponding control-values. Differences in the absolute amounts of glycogen and protein between control and drug-treated worms were even more pronounced. Administration of a subcurative dose of TIOX to the rat produced in H. diminuta another change, the onset of which preceded the gross alterations in worm weight and chemical composition. In vitro studies, carried out 18 hr after treatment, revealed that TIOX-treated worms absorbed and metabolized much smaller quantities of exogenous glucose than did the controls and that the ability of the worm to accumulate glucose against a concentration difference was significantly depressed. A mode of action common to the structurally related benzothiazole and benzimidazole anthelmintics is indicated by the similarity of their biochemical and physiological effects on the tapeworms and their time course of action when administered to rats infected with H. diminuta. Molecular modeling revealed that the benzothiazole and benzimidazole anthelminitics are congruent electronically and structurally. In vivo drug efficacy depends upon the magnitude of the molecular dipole moment and the percentage of polar surface area. Within the benzimidazole series, structural and electronic congruence is found between the 2-thiazolyl and 2-methyl carbamate groups, suggesting that these groups behave similarly in transport to, and binding at, the active site. Finally, anthelmintics that have the 5' substituents twisted out-of-plane were more active than those anthelminitics with 5' substituents in-plane. All of these factors implicate a highly polar, L-shaped cleft to which the anthelmintics bind at the active site.
本文报道了对驱虫药噻苯咪唑（TIOX，6 - [正丙氧基]苯并噻唑 - 2 - 氨基甲酸甲酯）对实验感染大鼠体内微小膜壳绦虫生化作用的研究。TIOX对微小膜壳绦虫的体内化疗作用伴随着虫体重量和化学成分的显著变化。从24小时前接受过治疗有效剂量TIOX的大鼠体内回收的绦虫明显小于未治疗对照组的绦虫，且糖原含量（占湿重的百分比）也少得多。在经TIOX处理的绦虫中，蛋白质浓度上升的速率足以抵消糖原浓度的下降。经TIOX处理的绦虫中糖原/蛋白质比值远低于相应的对照值。对照绦虫和经药物处理的绦虫之间糖原和蛋白质绝对量的差异更为明显。给大鼠施用亚治疗剂量的TIOX在微小膜壳绦虫中产生了另一种变化，其出现早于虫体重量和化学成分的总体改变。在处理后18小时进行的体外研究表明，经TIOX处理的绦虫吸收和代谢的外源性葡萄糖量比对照绦虫少得多，并且绦虫逆浓度差积累葡萄糖的能力明显降低。结构相关的苯并噻唑和苯并咪唑驱虫药对绦虫的生化和生理作用及其作用时间进程的相似性表明了它们共有的作用方式。分子建模显示苯并噻唑和苯并咪唑驱虫药在电子和结构上是一致的。体内药物疗效取决于分子偶极矩的大小和极性表面积的百分比。在苯并咪唑系列中，2 - 噻唑基和2 - 氨基甲酸甲酯基团之间存在结构和电子一致性，表明这些基团在转运至活性位点并与之结合时表现相似。最后，5'取代基扭曲出平面的驱虫药比5'取代基在平面内的驱虫药更具活性。所有这些因素都表明存在一个高度极性的L形裂隙，驱虫药在活性位点与之结合。
