期刊
BIOORGANIC CHEMISTRY
卷 124, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105855
关键词
Coumarin; Thiazole; Membrane; Resistance
资金
- National Natural Science Foundation of China [21971212, 81902357]
- Nat-ural Science Foundation of Chongqing [cstc2020jcyj-msxmX0004]
- Chongqing Research Program of Basic Research and Frontier Technol-ogy [cstc2018jcyjAX0518]
A novel type of coumarin thiazoles were synthesized and exhibited favorable inhibitory potency against various strains, especially methicillin-resistant Staphylococcus aureus (MRSA). The active compound showed low toxicity towards mammalian cells, effectively eradicated MRSA biofilms, and had a low probability of engendering drug resistance.
A novel type of coumarin thiazoles as unique multi-targeting antimicrobial agents were developed through four steps including cyclization, nucleophilic substitution and condensation starting from commercial resorcine. Most of the prepared coumarin thiazoles displayed favorable inhibitory potency against the tested strains. Noticeably, methyl oxime V -a exerted potent inhibitory efficacy against methicillin-resistant Staphylococcus aureus (MRSA) at low concentration (1 mu g/mL) and showed broad antimicrobial spectrum. Medicinal bioevaluations revealed that the active molecule V -a exhibited low toxicity toward mammalian cells, rapidly killing effect, good capability of eradicating MRSA biofilms and unobvious probability to engender drug resistance. Chemical biological methods were employed to investigate preliminary mechanism, which indicated that compound V -a was able to damage the integrity of membrane to trigger leakage of protein, insert into MRSA DNA to block its replication and induce the generation of reactive oxygen species (ROS) to inhibit bacterial growth. Computational study manifested that low HOMO-LUMO energy gap of molecule V -a was favorable to exert high antimicrobial activity.
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