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Novel organophosphorus aminopyrimidines as unique structural DNA-targeting membrane active inhibitors towards drug-resistant methicillin-resistant Staphylococcus aureus

Abstract

A series of novel unique structural organophosphorus aminopyrimidines were developed as potentially DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some prepared compounds displayed antibacterial activities. Particularly, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg/mL in comparison with the clinical chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had ability to rapidly kill the tested strains without obvious triggering the development of bacterial resistance, and showed low toxicity to L929 cells and could disturb cell membrane. Molecular docking study discovered that compound 2c could bind with DNA gyrase by hydrogen bonds and other weak interactions. The further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert the powerful antibacterial effects.

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Publication details

The article was received on 15 Jun 2018, accepted on 29 Jul 2018 and first published on 01 Aug 2018


Article type: Research Article
DOI: 10.1039/C8MD00301G
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Novel organophosphorus aminopyrimidines as unique structural DNA-targeting membrane active inhibitors towards drug-resistant methicillin-resistant Staphylococcus aureus

    D. Li, R. R. Y. Bheemanaboina, N. Battini, V. K. R. T., X. Fang and C. Zhou, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00301G

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