Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine. Issue 10 (1st June 2018)

• Record Type: Journal Article
• Authors: Liu, Jingru; Ma, Ruxin; Bi, Fangchao; Zhang, Fa; Hu, Chaoyu; Venter, Henrietta; Semple, Susan J.; Ma, Shutao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 10(2018)
• Page Start: 1825
• Page End: 1831
• Publication Date: 2018-06-01
• Subjects: Antibacterial activity -- FtsZ-targetingantibacterial agents -- 5-Methyl-2-phenylphenanthridium derivatives -- Structural simplification; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.04.015
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Novel 5-methyl-2-phenylphenanthridium derivatives were designed, synthesized and evaluated as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine. Highlights: 5-Methyl-2-phenylphenanthridium derivatives were designed, synthesized and evaluated. The newly synthesized derivatives showed a broad spectrum of potent antibacterial activity. Time-killing curves displayed the bactericidal effect. The ternary pyridinium derivatives could disrupt the polymerization of BsFtsZ. Molecular docking suggested that the binding site was a narrow cleft. Abstract: A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2 μg/mL) and three resistant strains (0.25–4 μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.