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Facile Preparation of 4-Substituted Quinazoline Derivatives
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2-Carboxyquinoline Boronic Acids as Highly Potent KPC Inhibitors
Zheng Ma1, Ge Cui1, Lijie Dou1
1State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P.R. China.
Chemmedchem
|December 27, 2024
Summary
Researchers discovered novel 2-carboxyquinoline boronic acids that inhibit Klebsiella pneumoniae carbapenemase (KPC). Compound 1e effectively combats KPC-2 resistance, restoring antibiotic efficacy against resistant Klebsiella pneumoniae.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Klebsiella pneumoniae carbapenemase (KPC) confers resistance to carbapenems, critical last-resort antibiotics.
- Rising antimicrobial resistance necessitates novel therapeutic strategies against Gram-negative bacterial infections.
Purpose of the Study:
- To discover and characterize novel inhibitors of KPC.
- To evaluate the potential of these inhibitors in restoring antibiotic efficacy against resistant bacteria.
Main Methods:
- Synthesis and screening of 2-carboxyquinoline boronic acid derivatives.
- Enzyme inhibition assays (IC50 determination) against KPC-2 and other β-lactamases.
- Cytotoxicity, haemolysis, and antibacterial activity assessments.
- In vitro potentiation of β-lactam antibiotics against resistant Klebsiella pneumoniae.
Main Results:
- Fluoro-substituted carboxyquinoline boronic acid 1e emerged as a potent KPC-2 inhibitor (IC50 = 8.3 nM).
- Compound 1e demonstrated selectivity, with reduced activity against other β-lactamases.
- Low cytotoxicity, haemolysis, and intrinsic antibacterial activity were observed for 1e.
- Compound 1e significantly potentiated meropenem and ceftazidime efficacy against KPC-2-expressing Klebsiella pneumoniae (up to 256-fold).
Conclusions:
- 2-Carboxyquinoline boronic acids represent a promising class of KPC inhibitors.
- Compound 1e shows potential as an adjuvant therapy to overcome carbapenem resistance.
- Further development could lead to new treatments for infections caused by KPC-producing bacteria.
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