Aminobenzylated 4‑Nitrophenols as Antibacterial Agents Obtained from 5‑Nitrosalicylaldehyde through a Petasis Borono–Mannich Reaction

Multidrug-resistant
bacteria are one of the current biggest threats
to public health and are responsible for most nosocomial infections.
Herein, we report the efficient and facile synthesis of antibacterial
agents aminoalkylphenols, derived from 5-nitrosalicyladehyde and prepared
through a Petasis borono–Mannich multicomponent reaction. Minimum
inhibitory concentrations (MICs) as low as 1.23 μM for a chlorine
derivative were determined for multidrug-resistant Gram-positive bacteria,
namely, Staphylococcus aureus and Enterococcus faecalis, two of the main pathogens
responsible for infections in a hospital environment. The most promising
antibacterial agents were further tested against eight strains of
four Gram-positive species in order to elucidate their antibacterial
broadness. In vitro cytotoxicity assays of the most active aminoalkylphenol
revealed considerably lower toxicity against mammalian cells, as concentrations
one order of magnitude higher than the determined MICs were required
to induce human keratinocyte cell death. The phenol moiety was verified
to be important in deeming the antibacterial properties of the analyzed
compounds, although no correlation between such properties and their
antioxidant activity was observed. A density functional theory computational
study substantiated the ability of aminoalkylphenols to serve as precursors
of ortho-quinone methides.