4,6-二氨基-1,2-二氢-1,3,5-三嗪溶液相组合文库的合成以及针对恶性疟原虫A16V+S108T突变型二氢叶酸还原酶新先导化合物的鉴定。

Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro-1,3,5-triazine and identification of new leads against A16V+S108T mutant dihydrofolate reductase of Plasmodium falciparum.

作者信息

Vilaivan Tirayut, Saesaengseerung Neungruthai, Jarprung Deanpen, Kamchonwongpaisan Sumalee, Sirawaraporn Worachart, Yuthavong Yongyuth

机构信息

Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand.

出版信息

Bioorg Med Chem. 2003 Jan 17;11(2):217-24. doi: 10.1016/s0968-0896(02)00344-9.

DOI:10.1016/s0968-0896(02)00344-9

PMID:12470716

Abstract

An efficient method to synthesize solution-phase combinatorial library of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazine was developed. The strategy involved an acid-catalyzed cyclocondensation between arylbiguanide hydrochlorides and carbonyl compounds in the presence of triethyl orthoacetate as water scavenger. A 96-membered combinatorial library was constructed from 6 aryl biguanides and 16 carbonyl compounds. Screening of the library by iterative deconvolution method revealed two candidate leads which are equally active against wild-type Plasmodium falciparum dihydrofolate reductase, but are about 100-fold more effective against the A16V+S108T mutant enzyme as compared to cycloguanil.

摘要

开发了一种高效合成1-芳基-4,6-二氨基-1,2-二氢-1,3,5-三嗪溶液相组合文库的方法。该策略涉及在原乙酸三乙酯作为脱水剂存在的情况下，芳基双胍盐酸盐与羰基化合物之间的酸催化环缩合反应。由6种芳基双胍和16种羰基化合物构建了一个96元的组合文库。通过迭代去卷积法对文库进行筛选，发现了两种候选先导化合物，它们对野生型恶性疟原虫二氢叶酸还原酶具有同等活性，但与环氯胍相比，对A16V + S108T突变酶的效力约高100倍。