萘酰肼类化合物的合成设计及其抑制克鲁斯氏锥体虫半胱氨酸蛋白酶的活性  

Design and synthesis of naphthylacyl hydrazides and their anticruzain activities

作　　者：程卯生[1] 张莉[1] 闫冬[1] 陈娥功 沈建民[1] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]青岛爱华海洋药业有限公司,山东青岛266100

出　　处：《中国药物化学杂志》2002年第4期187-193,共7页Chinese Journal of Medicinal Chemistry

摘　　要：目的卡格氏病 (Chagas′disease)是由克鲁斯氏锥体虫引起的一种寄生虫病 ,克鲁斯氏锥体虫半胱氨酸蛋白酶 (cruzain)是锥体虫生活周期中起重要作用的一种酶 ,研究该酶的抑制剂可望发展出一类治疗卡格氏病的新药。方法采用DOCK程序对前期研究中的抑酶活性最强的萘酰肼化合物z1与cruzain拟合的情况进行了研究 ,辅助指导药物分子设计和化学结构修饰 ,设计了 7个目标化合物z2～z8,并采用酶法体外筛选测定其抗克鲁斯氏锥体虫活性。结果以 2 ,3 二羟基萘为起始原料 ,经甲醚化保护、硝化、还原、氮甲基化、甲酰化、脱保护基和缩合等共 7步反应 ,制得目标化合物N′ (2 ,3 二羟基 4 二甲氨基 1 萘亚甲基 ) 3 羟基 2 萘甲酰肼 (z7) ,其抑制cruzain的IC50 值约为 0 2 0 μmol L ,其活性强度是化合物z1的两倍多。结论目标化合物经1 H NMR和MS确定了其化学结构。目标化合物z7的抑制酶的活性大大增强 。Aim The Chagas′ disease is caused by parasite Trypanosoma cruzi .We tried to do basic research on developing new antiparasitic drugs to inhibit the new drug target of cysteine protein,cruzain,which is an enzyme having a known structure and playing an important role in the life cycle of Trypanosoma cruzi.Methods Compound z1 was the best active candidate in the former research.Based on a known X ray structure of cruzain,we studied the putative binding orientation of compound z1 to the active sites of cruzain by the DOCK program to achieve the further modification of hydrazides.Seven target hydrazides(z2～z8)were designed and synthesized.Their anticruzi activities were evaluated by an assay of the cysteine protease cruzain.Results The target compound z7, N′ (2,3 dihydroxy 4 dimethylamino 1 naphthyl methylene) 3 hydroxy 2 naphthoichydrazide,was obtained from a start material 2,3 dihydroxynaphthalene through a seven step reaction sequence,including O methylation,nitration,reduction, N dimethylation,formylation,deprotection and condensation.Compound z7 gave better inhibition against cruzain with an IC 50 value of 0 20 μmol/L.Its anticruzi activity increased 2 times more than that of z1.Conclusion The structures of all the compounds were identified by 1H NMR and MS spectra.The target compound z7 gave better bioactivity as the computer prediction.

关 键 词：萘酰肼类化合物 克鲁斯氏锥体虫半胱氨酸蛋白酶 抑制 

分 类 号：R914[医药卫生—药物化学]