Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme N-Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics
Year: 2024
Type: article
Abstract: Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d bears an aminopyridine amide with an IC50 of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog 7q has an IC50 of 18.8 µM, with potency residing in the (R)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor (R)-7q with Tm = 50.2 °C and a Ki of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions.
DOI: 10.3390/ijms26010022
Institution: Loyola University Chicago
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,296
Funder: Loyola University Chicago
OpenAlex ID: W4405735711