Synthesis and biological evaluation of coumarin derivatives containing imidazole skeleton as potential antibacterial agents

• Published in: European journal of medicinal chemistry Vol. 143; pp. 958 - 969
• Main Authors: Hu, Yang, Shen, Yufeng, Wu, Xiaohu, Tu, Xiao, Wang, Gao-Xue
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2018; Elsevier
• Subjects: Antibacterial activity; Chemistry, Medicinal; Coumarin derivatives; FabI; FabK; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Antibacterial activity; Coumarin derivatives; FabI; FabK; BACTERIA; Fabl; ANTICANCER ACTIVITIES; HIV; ANALOGS; MALARIA; TARGETS; RESISTANT STAPHYLOCOCCUS-AUREUS; HYBRIDS
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2017.11.100

Emergence of multidrug-resistant bacteria causes an urgent need for new generation of antibiotics, which may have a different mechanism of inhibition or killing action from the existing. Here, we report on the design, synthesis, and biological evaluation of thirty-nine coumarin derivatives in order to solve the antibacterial resistance by targeting at the inhibition of biosynthesis pathway of fatty acids. Their antibacterial activities against Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Flavobacterium cloumnare are tested and action mechanism against the key enzyme in bacterial fatty acid synthesis pathway are studied. The results show that compounds 13 and 18 have potent and broad spectrum antimicrobial activity. In addition, 9, 14 and 19 show eminent antimicrobial efficacy toward S. aureus, S. agalactiae, and F. cloumnare. Mechanistically, coumarin derivatives display the antibacterial activity via the control of FabI and FabK function. The structure-activity relationship analysis indicate that the length of linker and imidazole substitute group could significantly influence the antimicrobial activity, as well as the inhibitory activity against FabI and FabK. The structural optimization analysis of coumarin suggest that derivatives 9, 13, 14, 18 and 19 could be a viable way of preventing and controlling bacteria and considered as promising lead compounds for the development of commercial drugs. [Display omitted] •Novel coumarin-imidazoles with antibacterial properties were synthesized.•Coumarin derivatives showed the antibacterial activity by inhibiting the FabI and FabK.•Structure-activity relationship showed the importance of the alkyl linker and imidazole.