ABSTRACT
Background: Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cyclopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, first indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identified with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspective small-molecule antibacterial drug candidates.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus/drug effects , Hydrocarbons, Brominated/pharmacology , Hydrocarbons, Iodinated/pharmacology , Small Molecule Libraries/pharmacology , Staphylococcus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Hydrocarbons, Brominated/chemical synthesis , Hydrocarbons, Brominated/chemistry , Hydrocarbons, Iodinated/chemical synthesis , Hydrocarbons, Iodinated/chemistry , Microbial Sensitivity Tests , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistryABSTRACT
Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Infections with Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) have become more difficult to treat with standard antibiotics that often fail, especially against MRSA. In consequence, novel antibiotics are urgently needed. Antibiotics from natural sources own complicated structures that cause difficulties for a chemical synthetic production. We developed novel small-molecule antibacterials that are easily accessible in a simple one-pot synthesis. The central indolonaphthalene core is substituted with indole residues at various positions. Both the varied indole substitutions and their positions at the molecular scaffold influence the determined antibacterial activity against the evaluated Staphylococcus strains. Best activities have been found for 5-chloro, -cyano, and -hydroxyl indole substitutions. Therefore, first promising lead compounds could be identified that are nontoxic in human HEK and SH-SY5Y cells and exceed the activity of used standard antibiotics, especially against MRSA.
