The structure – Activity correlation in the family of dicationic imidazolium
surfactants: Antimicrobial properties and cytotoxic effect
Alexandra D. Voloshinaa, Syumbelya K. Gumerovaa, Аnastasiia S. Sapunovaa, Natalia V. Kulika,
Alla B. Mirgorodskayaa,⁎, Alla A. Kotenkob, Tatiana M. Prokopyevab, Vasilii A. Mikhailovb,
Lucia Ya Zakharovaa, Oleg G. Sinyashina
a Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str., 8, Kazan 420088, Russia
b L.M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, 70 R. Luxemburg St., 83114 Donetsk, Ukraine
A R T I C L E I N F O
Keywords:
Dicationic imidazolium surfactants
Antimicrobial activity
Cytotoxicity
Hemolysis
Resistance
Apoptosis
A B S T R A C T
Background: The development of new effective microbicide surfactants and the search for the structure–biological
activity relationship is an important and promising problem. Surfactants containing imidazolium
fragment attract attention of researchers in the field of chemotherapy, because these compounds often exhibit
high antimicrobial activity. The aim of this work is to identify the newly synthesized surfactants from the
viewpoint of their potential usefulness in pharmacology and medicine. For this purpose, a detailed study of
antimicrobial, hemolytic and cytotoxic activity of dicationic alkylimidazolium surfactants of the m-s-m (Im)
series with a variable length of a hydrocarbon tail (m = 10, 12) and a spacer fragment (s = 2, 3, 4) was carried
out.
Methods: Aggregation of surfactants in solutions was estimated by tensiometry and conductivity. Antimicrobial
activity was determined by the serial dilution technique. Cytotoxic effects of the test compounds on human
cancer and normal cells were estimated by means of the multifunctional Cytell Cell Imaging system. Cell
Apoptosis Analysis was made by flow cytometry.
Results: The test compounds show high antimicrobial activity against a wide range of test microorganisms and
do not possess high hemolytic activity. Importantly, some of them display a bactericidal activity comparable to
ciprofloxacin fluoroquinolone antibiotic against Gram-positive bacteria, including methicillin-resistant strains of
S. aureus (MRSA). The cytotoxicity of the compounds against normal and tumor human cell lines has been tested
as well, with cytotoxic effect and selectivity strongly controlled by structural factor and kind of cell line. Superior
results were revealed for compound 10–4-10 (Im) in the case of HuTu 80 cell line (duodenal adenocarcinoma),
for which IC50 value at the level of doxorubicin and a markedly higher selectivity index (SI 7.5) were demonstrated.
Flow cytometry assay shows apoptosis-inducing effect of this compound on HuTu 80 cells, through
significant changes in the potential of mitochondrial membrane.
Major conclusions: Antibacterial properties are shown to be controlled by alkyl chain length, with the highest
activity demonstrated by surfactants with decyl tail, with the length of the spacer fragment showing practically
no effect. The results indicate that the mechanism of cytotoxic effect of the compounds can be associated with
the induction of apoptosis via the mitochondrial pathway.
General significance: Selectivity against pathogenic microorganisms and low toxicity against eukaryotic cells
allow considering dicationic imidazolium surfactants as new effective antimicrobial agents. At the same time,
high selectivity against some cancer cell lines indicates the prospect of their using as components of new anticancer
drugs.
