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. 2022 Jan 24;27(3):757.
doi: 10.3390/molecules27030757.

Antimicrobial, Cytotoxic and Mutagenic Activity of Gemini QAS Derivatives of 1,4:3,6-Dianhydro-l-iditol

Karol Sikora  1   2 , Andrzej Nowacki  2 , Piotr Szweda  3 , Anna Woziwodzka  4 , Sylwia Bartoszewska  1 , Jacek Piosik  4 , Barbara Dmochowska  2
Affiliations

Antimicrobial, Cytotoxic and Mutagenic Activity of Gemini QAS Derivatives of 1,4:3,6-Dianhydro-l-iditol

Karol Sikora et al. Molecules. .

Abstract

A series of quaternary diammonium salts derivatives of 1,4:3,6-dianhydro-l-iditol were synthesized, using isommanide (1,4:3,6-dianhydro-d-mannitol) as a starting material. Both aromatic (pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), (3-carboxamide)pyridine; N-methylimidazole) and aliphatic (trimethylamine, N,N-dimethylhexylamine, N,N-dimethyloctylamine, N,N-dimethyldecylamine) amines were used, giving eight gemini quaternary ammonium salts (QAS). All salts were tested for their antimicrobial activity against yeasts, Candida albicans and Candida glabrata, as well as bacterial Staphylococcus aureus and Escherichia coli reference strains. Moreover, antibacterial activity against 20 isolates of S. aureus collected from patients with skin and soft tissue infections (n = 8) and strains derived from subclinical bovine mastitis milk samples (n = 12) were evaluated. Two QAS with octyl and decyl residues exhibited antimicrobial activity, whereas those with two decyl residues proved to be the most active against the tested pathogens, with MIC of 16-32, 32, and 8 µg/mL for yeast, E. coli, and S. aureus reference and clinical strains, respectively. Only QAS with decyl residues proved to be cytotoxic in MTT assay against human keratinocytes (HaCaT), IC50 12.8 ± 1.2 μg/mL. Ames test was used to assess the mutagenic potential of QAS, and none of them showed mutagenic activity in the concentration range 4-2000 µg/plate.

Keywords: 1,4:3,6-dianhydro-d-mannitol; antimicrobial activity; gemini; mutagenicity; quaternary ammonium salts.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Synthesis of gemini QAS derivatives of 1,4:3,6-dianhydro-l-iditol. Reaction conditions: (a) pyridine, 48 h, RT; (b) DMAP, CH3CN, 48 h 40 °C; (c) pyridinie-3-carboxamide, CH3CN, 7 days, 70 °C; (d) N-methylimidazole, 24 h, RT; (e) trimethylamine in ethanol, 48 h, 40 °C; (f) N,N-dimethylhexylamine, CH3CN, 24 h, 70 °C; (g) N,N-dimethyloctylamine, CH3CN, 24 h, 70 °C; (h): N,N-dimethyldecylamine, CH3CN, 24 h, 70 °C.
Figure 1
Figure 1
Structure and proton chemical shifts in 1H NMR spectra of N-methylimidazole moiety of QAS 6.
Figure 2
Figure 2
Mutagenic activity of QAS 3–8 presented as % of positive control (doxorubicin, 90 ng/plate) in Ames test with Salmonella typhimurium TA 98 strain.
See this image and copyright information in PMC

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