Synthesis of 1,3,4-trisubstituted pyrrolidines as meropenem adjuvants targeting New Delhi metallo-β-lactamase
| Autor: | Chen Xu, Yun Chung Leung, Sheng Chen, Wen Bin Jin, Tak Hang Chan, Edward Wai-Chi Chan, Wei Gao, Kin-Fai Chan, Ki Hon Lai, Ping Zeng, Kwok Yin Wong, Jiachi Chiou, Xiao Lin Qi |
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| Rok vydání: | 2021 |
| Předmět: |
Carbapenem
medicine.drug_class Antibiotics 010402 general chemistry 01 natural sciences Meropenem Catalysis 03 medical and health sciences Materials Chemistry medicine Cytotoxicity IC50 chemistry.chemical_classification 0303 health sciences biology 030306 microbiology Active site General Chemistry biology.organism_classification Combinatorial chemistry Enterobacteriaceae 0104 chemical sciences Enzyme chemistry biology.protein medicine.drug |
| Zdroj: | New Journal of Chemistry. 45:3515-3534 |
| ISSN: | 1369-9261 1144-0546 |
| DOI: | 10.1039/d0nj06090a |
| Popis: | The effective strategies to neutralize the New Delhi metallo-β-lactamase (NDM-1) activity offer unique opportunities to combination therapy because NDM-1 inactivates all classes of carbapenem antibiotics, which are widely regarded as the last resort of drugs for treating serious bacterial infections. Here we describe the efficient construction of a series of trans-1,3,4-trisubstituted pyrrolidines via boric acid-catalyzed 1,3-dipolar cycloaddition of N-benzylazomethine ylide with methyl ferulate for the biological evaluation of their cytotoxicity and synergistic activity in combination with meropenem towards NDM-1 positive carbapenem-resistant Enterobacteriaceae (CRE). The cell-based screens generated one promising hit, namely compound 10e, which exhibited low cytotoxicity (IC50 > 128 μM), moderate NDM-1 enzyme inhibition (IC50 = 51 μM), and potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE with fractional inhibitory concentration indexes ranging from 0.01 to 0.25. Structure–activity relationship studies revealed that the zinc-chelating moiety of 2-(bis(pyridin-2-ylmethyl)-amino)acetyl group of compound 10e plays a pivotal role for potent activity. Regarding the inhibition mechanism, a series of biochemical assays revealed that compound 10e may inactivate NDM-1 activity by displacing both zinc ions from the active site of the enzyme. Altogether, our studies indicate that compound 10e represents an important pyrrolidine-type scaffold targeting NDM-1, providing a promising starting point to be further developed as carbapenem antibiotic adjuvants. |
| Databáze: | OpenAIRE |
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