Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling.

Vitamin K antagonists (VKAs) anticoagulants have been used since the 1950s as medicines and rodenticides. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide reductase (VKORC1), an endoplasmic reticulum membrane resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus treatments failures.

Synthesis and biological evaluation of C-3 aliphatic coumarins as vitamin K antagonists.

Since the discovery of Warfarin in the 1940s, the design of new warfarin-derived anticoagulants for rodent management has been challenging, with mainly structural modifications performed on the C3 position of the coumarin skeleton. In order to better understand the pharmacomodulation of such derivatives, we have synthesized a family of C3 (linear and branched) alkyl-4-hydroxycoumarins, which led to the identification of compounds 5e and 5f as potential short-term active anticoagulants.

New insights into the catalytic mechanism of vitamin K epoxide reductase (VKORC1) - The catalytic properties of the major mutations of rVKORC1 explain the biological cost associated to mutations.

The systematic use of antivitamin K anticoagulants (AVK) as rodenticides caused the selection of rats resistant to AVKs. The resistance is mainly associated to genetic polymorphisms in the Vkorc1 gene encoding the VKORC1 enzyme responsible for the reduction of vitamin K 2,3-epoxide to vitamin K. Five major mutations, which are responsible for AVK resistance, have been described.

3-Aryl-4-methyl-2-quinolones targeting multiresistant Staphylococcus aureus bacteria.

The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI).