Design, synthesis and biological evaluation of novel glyoxamide based antibacterial agents

Abstract

Antimicrobial resistance is becoming increasingly prevalent due to the ability of bacteria to transfer genes encoding resistant mechanisms. Thereby, conventional antibiotics are becoming ineffective against various microorganisms including bacteria. Therefore, there is an urgent need for the development of antibacterial agents with novel therapeutic actions. Bacteria cooperatively regulate the expression of many phenotypes such as biofilm formation and virulence factor expression through a mechanism called quorum sensing (QS). Antimicrobial peptides (AMPs) are a key component of the mammalian defense system that provides protection against various pathogens. Thus, the development of novel quorum-sensing inhibitors and AMP mimics are viable strategies to counteract the increasing incidence of antimicrobial resistance. The current research work focussed on the design and synthesis of novel acyclic and cyclic glyoxamide derivatives via the ring-opening reactions of N-arylisatins and N-acylisatins with amines and amino acid esters. These compounds were investigated for quorum sensing inhibition (QSI) activity against Pseudomonas aeruginosa MH602 and Escherichia coli MT102. The most active compound inhibited GFP fluorescence production by 48.7% in P. aeruginosa MH602 and 73.6% in E. coli MT102, at 250 μM, respectively. Also, pyocyanin and biofilm inhibition activities of these glyoxamide compounds were determined in P. aeruginosa and E. coli, and these compounds possessed greatest pyocyanin inhibition activity with 47% inhibition against P. aeruginosa and significant biofilm inhibition (40-71%) against P. aeruginosa and E. coli, at 250 μM, respectively. In addition, various glyoxamide based AMP mimics derived from the ring-opening reactions of N-naphthoylisatin have also been reported in this work. The antibacterial activity of these glyoxamide derivatives was investigated against Staphylococcus aureus and E. coli by their zoneof- inhibition and the determination of minimum inhibitory concentration (MIC). The most active compounds exhibited greatest MIC values with 6 μg/mL and 17 μg/mL against S. aureus and E. coli, respectively. Furthermore, these compounds showed significant biofilm inhibition (40-65%) and disruption (40-72%) activities against both Gram-positive and Gram-negative bacteria. Finally, the in vitro toxicity of these compounds against human lung fibroblast cells revealed that these compounds are less toxic to human cells.