Increased antibacterial properties of indoline-derived phenolic Mannich bases

• DOI: 10.1016/j.ejmech.2021.113459
• Publication Date: 2021-04-20T17:50:44Z
• Authors: Tatu Rimpiläinen; Alexandra Nunes; Rita Calado; Ana S. Fernandes; Joana Andrade; Epole Ntungwe; Gabriella Spengler; Nikoletta Szemerédi; João Rodrigues; João Paulo Gomes; Patricia Rijo; Nuno R. Candeias
• Keywords: 0301 basic medicine; Indoles; Cell Survival; 116 Chemical sciences; 610; 116; Microbial Sensitivity Tests; Gram-Positive Bacteria; Antioxidants; Cell Line; Mannich Bases; Structure-Activity Relationship; 03 medical and health sciences; Phenols; Picrates; Animals; Humans; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Biphenyl Compounds; 500; 03.01. Általános orvostudomány; Anti-Bacterial Agents; 3. Good health; Artemia

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 (Staphylococcus aureus, S. epidermidis, Enterococcus faecalis, E. faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro 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.