Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study.
Résumé
New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phos-phorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four serieshave been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyc-lic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tri-cyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction.Compared to7-DXused as control,2d,2l,2p(series A),28a(series D), and the open intermediate30showed modest to good activities. A kinetic study confirmed that the most active compounds2d,2parecompetitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds atthe active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yetbeen explored.
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