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

  • ACS Comb Sci. 2018 Jan 8;20(1):35-43. doi: 10.1021/acscombsci.7b00163.
Andrey V Bogolubsky  1 ,  Yurii S Moroz  1  2 ,  Olena Savych  1  2 ,  Sergey Pipko  1  2 ,  Angelika Konovets  1  2 ,  Maxim O Platonov  1 ,  Oleksandr V Vasylchenko  1 ,  Vasyl V Hurmach  1  2 ,  Oleksandr O Grygorenko  1  2
Affiliations
  • 1. Enamine Ltd. , 78 Chervonotkatska Street, Kyiv 02094, Ukraine.
  • 2. National Taras Shevchenko University of Kyiv , 60 Volodymyrska Street, Kyiv 01601, Ukraine.
PMID: 29227678 DOI: 10.1021/acscombsci.7b00163
Abstract

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-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.

Keywords
2,2,2-trifluoroethylcarbamates; amino esters; condensation; kinase inhibitors; nitrogen heterocycles.
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