Increased Antibacterial Properties of Indoline-Derived Phenolic Mannich Bases

<p>The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 µM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (<i>Staphylococcus aureus</i>, <i>S. epidermidis</i>, <i>Enterococcus</i> <i>faecalis</i>,<i> E. faecium</i>, and<i> Listeria monocytogenes</i>). The same two aminoalkylphenols displayed low toxicity against two <i>in vivo</i> models (<i>Artemia salina</i> brine shrimp and <i>Saccharomyces cerevisiae</i>)<i>. </i>The <i>in vitro</i> cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC₅₀ in the 1.7-5.1 mM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the alkylaminophenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the alkylaminophenols.</p>