Bioorganic & Medicinal Chemistry Letters 2013-04-01

Substituted 1,6-diphenylnaphthalenes as FtsZ-targeting antibacterial agents.

Yongzheng Zhang, Daniel Giurleo, Ajit Parhi, Malvika Kaul, Daniel S Pilch, Edmond J LaVoie

Index: Bioorg. Med. Chem. Lett. 23(7) , 2001-6, (2013)

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Abstract

Bacterial cell division occurs in conjunction with the formation of a cytokinetic Z-ring structure comprised of FtsZ subunits. Agents that disrupt Z-ring formation have the potential, through this unique mechanism, to be effective against several of the newly emerging multidrug-resistant strains of infectious bacteria. Several 1-phenylbenzo[c]phenanthridines exhibit notable antibacterial activity. Based upon their structural similarity to these compounds, a distinct series of substituted 1,6-diphenylnaphthalenes were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis. In addition, the effect of select 1,6-diphenylnaphthalenes on the polymerization dynamics of S. aureus FtsZ and mammalian β-tubulin was also assessed. The presence of a basic functional group or a quaternary ammonium substituent on the 6-phenylnaphthalene was required for significant antibacterial activity. Diphenylnaphthalene derivatives that were active as antibiotics, did exert a pronounced effect on bacterial FtsZ polymerization and do not appear to cross-react with mammalian tubulin to any significant degree.Copyright © 2013 Elsevier Ltd. All rights reserved.