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.
Keywords:
DapE; antibiotic; metalloenzyme; ninhydrin.
MeSH terms
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Amidohydrolases* / antagonists & inhibitors
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Amidohydrolases* / chemistry
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Amidohydrolases* / metabolism
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Anti-Bacterial Agents* / chemical synthesis
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Anti-Bacterial Agents* / chemistry
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Anti-Bacterial Agents* / pharmacology
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Bacterial Proteins / antagonists & inhibitors
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Catalytic Domain
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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Haemophilus influenzae* / drug effects
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Haemophilus influenzae* / enzymology
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Kinetics
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Molecular Docking Simulation*
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Pyrazoles* / chemical synthesis
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Pyrazoles* / chemistry
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Pyrazoles* / pharmacology
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Pyrazoles
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Amidohydrolases
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N-succinyl-l,l-diaminopimelic acid desuccinylase
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Enzyme Inhibitors
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Bacterial Proteins
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pyrazole