Optimizing the structure of (salicylideneamino)benzoic acids: Towards selective antifungal and anti-staphylococcal agents

Eur J Pharm Sci. 2021 Apr 1;159:105732. doi: 10.1016/j.ejps.2021.105732. Epub 2021 Jan 22.

Abstract

An increasing resistance of human pathogenic bacteria and fungi has become a global health problem. Based on previous reports of 4-(salicylideneamino)benzoic acids, we designed, synthesised and evaluated their me-too analogues as potential antimicrobial agents. Forty imines derived from substituted salicylaldehydes and aminobenzoic acids, 4-aminobenzoic acid esters and 4-amino-N-phenylbenzamide were designed using molecular hybridization and prodrug strategies. The target compounds were synthesized with high yields and characterized by spectral methods. They were investigated against a panel of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts and moulds. The most active imines were tested to determine their cytotoxicity and selectivity in HepG2 cells. Dihalogenosalicylaldehydes-based derivatives showed potent broad-spectrum antimicrobial properties, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 7.81 µM) and Enterococcus faecalis (MIC of ≥15.62 µM), yeasts (MIC from 7.81 µM) and Trichophyton interdigitale mould (MIC of ≥3.90 µM). Methyl 4-[(2-hydroxy-3,5-diiodobenzylidene)amino]benzoate 4h exhibited excellent in vitro activity along with low toxicity to mammalian cells. This compound is selective for staphylococci, Candida spp. and Trichophyton interdigitale. In addition, this imine was evaluated as a potential inhibitor of Gram-positive biofilms. The successful approach used provided some promising derivatives with more advantageous properties than the parent 4-(salicylideneamino)benzoic acids.

Keywords: Aminobenzoic acids; Schiff bases; anti-biofilm activity; antibacterial activity; antifungal activity; cytotoxicity.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Antifungal Agents* / pharmacology
  • Arthrodermataceae
  • Benzoates / pharmacology
  • Gram-Negative Bacteria
  • Gram-Positive Bacteria
  • Humans
  • Methicillin-Resistant Staphylococcus aureus*
  • Microbial Sensitivity Tests
  • Molecular Structure

Substances

  • Anti-Bacterial Agents
  • Antifungal Agents
  • Benzoates

Supplementary concepts

  • Trichophyton interdigitale