PYRIMIDINE SCAFFOLD MOLECULES AS POTENTIAL HLDHA INHIBITORS

Abstract

[ESEl objetivo del presente trabajo es diseñar una serie de moléculas con núcleo de pirimidina como potenciales inhibidores de hLDHA, para ello se han sintetizado, caracterizado y evaluado su actividad inhibitoria tanto in – sílico como in – vitro. Se va a proponer una primera generación de moléculas con núcleo de pirimidina y posteriormente, a través de un proceso de docking molecular, van a ser optimizadas para determinar así una segunda generación de moléculas. Los derivados de pirimidina propuestos se han sintetizado siguiendo una ruta en tres pasos. Primero se prepararon las 2‐cloro‐4‐arilpirimidinas mediante reacción de acoplamiento C‐C. A continuación, se introduce el fragmento a modo de linker a través de una sustitución aromática nucleofílica y, finalmente, se añade el extremo polar de quinolona.

[EN]The main target of this work is to design a new series of pyrimidine‐based molecules as hLDHA inhibitors, that is to synthesize, characterize and evaluate their in – silico and in – vitro inhibitory activity. For this, we are going to propose a first pyrimidine – based generation and then, throughout a docking process, we are going to optimize them in order to get the second generation of the pyrimidine – based molecules. For the synthesis part, a three step pathway has been followed. Firstly, 2‐chloro‐4‐arilpyrimidines were synthesised throughout a Pd catalysed C – C cross‐coupling reaction, starting from the commercially available 2,4‐dichloropyrimidine. After that, a linker moiety was added by a nucleophilic aromatic substitution and finally the quinolone scaffold was incorporated by further substitution or condensation.