6533b85afe1ef96bd12b89e4
RESEARCH PRODUCT
false
subject
chemistry.chemical_classificationProteasesNucleophilic additionProtease010405 organic chemistryStereochemistryChemistrymedicine.medical_treatmentOrganic ChemistryKineticsPharmaceutical Science14-Naphthoquinone010402 general chemistry01 natural sciences0104 chemical sciencesAnalytical Chemistrychemistry.chemical_compoundEnzymeChemistry (miscellaneous)Covalent bondDrug DiscoverymedicineMolecular MedicinePhysical and Theoretical ChemistryCysteinedescription
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-04-28 | Molecules |