An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries

被引：16

作者：

Bogolubsky, Andrey V. ^{[1
]}

Moroz, Yurii S. ^{[1
,2
]}

Savych, Olena ^{[1
,2
,3
]}

Pipko, Sergey ^{[1
,2
]}

Konovets, Angelika ^{[1
,2
]}

Platonov, Maxim O. ^{[1
]}

Vasylchenko, Oleksandr V. ^{[1
]}

Hurmach, Vasyl V. ^{[1
,2
]}

Grygorenko, Oleksandr O. ^{[1
,2
]}

机构：

[1] Enamine Ltd, 78 Chervonotkatska St, UA-02094 Kiev, Ukraine

[2] Natl Taras Shevchenko Univ Kyiv, 60 Volodymyrska St, UA-01601 Kiev, Ukraine

[3] Natl Acad Sci Ukraine, Dept Chem Bioact Nitrogen Containing Heterocycl B, Inst Bioorgan Chem & Petrochem, UA-02094 Kiev, Ukraine

来源：

ACS COMBINATORIAL SCIENCE | 2018年 / 20卷 / 01期

关键词：

condensation; nitrogen heterocycles; 2,2,2-trifluoroethylcarbamates; amino esters; kinase inhibitors; SOLID-PHASE SYNTHESIS; MICROWAVE-ASSISTED SYNTHESIS; AURORA KINASE INHIBITORS; LEAD-ORIENTED SYNTHESIS; COMBINATORIAL CHEMISTRY; 1,3,5-TRISUBSTITUTED HYDANTOINS; SEQUENTIAL SYNTHESIS; CARBOXYLIC-ACIDS; FACILE SYNTHESIS; DRUG DISCOVERY;

D O I：

10.1021/acscombsci.7b00163

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and a-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.

引用

页码：35 / 43

页数：9

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