Synthesis, characterization and application of new imino-functionalized 1,3-diazolium salts as antimicrobial agents

Abstract

The simple solventless quaternization of N-substituted 1,3-diazoles with 2-bromoethyliminomethylnaphthol yielded three new Schiff base (SB or imine)-functionalized 1,3-diazolium [3 (SB-imidazolium), 4 and 5 (SB-benzimidazolium)] salts. The compounds were characterized spectroscopically, and the single-crystal solid-state structure of compound 3 [3-(2-(2-hydroxynaphthalen-1-yl) methylene) amino) ethyl) methylimidazol-3-ium hexafluorophosphate] was analyzed by X-ray diffraction. When tested as antimicrobials, each salt gave significant activity against the Gram-positive Staphylococcus aureus ATCC 25923 strain and the Methicinin resistant Staphylococcus aureus ATCC 700699 (MRSA) strain with the best minimum inhibitory concentration (MIC) value of 1.25 µg/mL recorded for 4. Although not as active as the positive control, Ciprofloxacin, the observed activities of the compounds are comparable to those reported for some standard antibiotics and significantly better than similar 1,3-diazolium salts that are already reported in the literature. The use of theoretical molecular docking supports the experimental MIC values for the salts. This is because the estimated negative binding energies of -6.45, -7.27 and -7.84, kcal/mol for 3, 4 and 5, respectively, indicated favourable binding with the MRSA lipase enzyme complexes. Furthermore, the results of a hemolytic assay corroborated the antimicrobial test results, which showed ≤5% hemolysis of red blood cells at the most active concentration (lowest MIC value) recorded for the salts. In summary, the results of the antibacterial activity study and the negative Gibbs binding energies that are within safe hemolysis percentages make the new azolium salts good templates in drug design.