Research ArticlePrediction of Antifungal Activity of GeminiImidazolium Compounds
Aukasz PaBkowski,1 Jerzy BBaszczyNski,2 Andrzej Skrzypczak,3
Jan BBaszczak,3 Alicja Nowaczyk,4 Joanna Wrblewska,5 Sylwia Kohuszko,5
Eugenia Gospodarek,5 Roman SBowiNski,2,6 and Jerzy KrysiNski1
1Department of Pharmaceutical Technology, Nicolaus Copernicus University, Jurasza 2, 85-094 Bydgoszcz, Poland2Institute of Computing Science, Poznan University of Technology, Piotrowo 2, 60-965 Poznan, Poland3Institute of Chemical Technology, Poznan University of Technology, Skodowskiej-Curie 2, 60-965 Poznan, Poland4Department of Organic Chemistry, Nicolaus Copernicus University, Jurasza 2, 85-094 Bydgoszcz, Poland5Department of Microbiology, Nicolaus Copernicus University, Skodowskiej-Curie 9, 85-094 Bydgoszcz, Poland6Systems Research Institute, Polish Academy of Sciences, Newelska 6, 01-447 Warsaw, Poland
Correspondence should be addressed to ukasz Pakowski; firstname.lastname@example.org
Received 21 October 2014; Revised 13 December 2014; Accepted 23 December 2014
Academic Editor: Lei Chen
Copyright 2015 ukasz Pakowski et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Sincecationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one ofthe major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features ofthese compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted withthe help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevantcombinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows,moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as wellas on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, totalstructure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds.
In recent years the number of applications of quaternaryammonium compounds (QACs) has increased considerably.Gemini QACs are a group of cationic surfactants containingtwo head groups and two aliphatic chains linked by a spacergroup.
Practical implementation of gemini QACs is a resultof their surface active, antielectrostatic, and antimicrobialproperties.
It has been demonstrated that gemini QACs exhibitproperties superior to mono QACs, such as better solubility,higher adsorption efficiency, and better wetting and foaming
. Gemini QACs are more efficient in lowering surfacetension and have much lower critical micelle concentration(CMC) . Due to their higher surface activity they haveexcellent dispersion stabilization and soil clean-up properties[6, 7]. It has been also demonstrated that gemini QACs havegood antifungal activity , which is higher than monoQACs [11, 12]. So it is worth developing new, more effectivecompounds, such as gemini QACs.
Because of the increasing resistance of microorganismsto commonly used disinfectants, the synthesis of new typesof microbicides is a very important topic . Formationof resistant strains of fungi is not as common as formationof resistant strains of bacteria . Nevertheless, knowledge
Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 392326, 10 pageshttp://dx.doi.org/10.1155/2015/392326
2 BioMed Research International
of properties of chemical compound, which influence theantifungal activity of gemini QACs, enables designing andsynthesis of new, active chemical entities.
Themain goal of our studywas to investigate relationshipsbetween selected molecular parameters and features describ-ing chemical structure and surface active properties andantifungal activity (described as MFC (minimal fungicidalconcentration)). In MFC study Candida albicans ATCC90028 strainwas used. In structure-activity relationship study(SAR), modified method, based on a rough set theory, wasemployed.
Candida albicans is one ofmajor opportunistic pathogenscausing a wide spectrum of diseases in human beings. It cancause infections that range from superficial infections of theskin to life-threatening systemic infections . Given thelimited number of suitable and effective antifungal agents,together with increasing drug resistance of the pathogens, itis important that new classes of antifungals are discovered. Moreover, better understanding of which features ofchemical compounds decide high antifungal activity mayprovide further information useful for the improvement ofantifungal action.
Data that describe the analyzed series of gemini imi-dazolium chlorides can be seen as classification data,where parameters characterizing structure and surface activeproperties, as well as molecular parameters, are conditionattributes (independent variables) and antifungal activityis represented by class labels assigned to chlorides by adecision attribute (dependent variable). Structure-activityrelationships can be discovered from these data by explainingthe class assignment in terms of condition attributes. To thisend, we applied the rough set concept , and its particularextension called Dominance-Based Rough Set Approach(DRSA) .
2. Materials and Methods
2.1. Gemini Imidazolium Chlorides. We analyzed 10 homolo-gous series of gemini imidazolium chlorides with hydropho-bic chain ranging from CH
and with the lengthof spacer from C
2to C12. Synthesis, surface active proper-
ties, and antimicrobial activity of a part of 140 3,3-(,-dioxaalkyl)bis(1-alkylimidazolium) chlorides were describedearlier . Moreover, we determined molecular descriptorsfor synthetized structures. The antifungal activity was deter-mined by theMFC values.The final stage of our study was ananalysis of structure-activity relationships using DRSA .
2.2. Chemical Structure. Chemical structure of chlorides wasdescribed by the following parameters (see Figure 1 andTable 1):
(i) : number of carbon atoms in -spacer,(ii) : number of carbon atoms in -substituent.
2.3. Surface Active Properties. Surface active properties ofanalyzed chlorides were described by the following param-eters:
Table 1: Numerical coding of the structure of analyzed chlorides.
Code Condition attributes-spacer -substituent
1 CH32 C2H5 C2H53 C3H7 C3H74 C4H9 C4H95 C5H11 C5H116 C6H13 C6H137 C7H15 C7H158 C8H17 C8H179 C9H19 C9H1910 C10H21 C10H2111 C11H2312 C12H25 C12H2514 C14H2916 C16H33
N NN+ N+
Figure 1: Chemical structure of analyzed compounds.
(i) CMC: critical micelle concentration (mol/L),(ii) CMC: value of surface tension at critical micelle
concentration (mN/m),(iii) 106 (G): value of surface excess (mol/m2),(iv) 1020: molecular area of a single particle (m2),(v) ads: free energy of adsorption ofmolecule (kJ/mol).
2.4. Molecular Parameters. We also considered molecularparameters of analyzed compounds, which were calculatedwith Dragon and Gaussian software. Molecular descriptor isthe final result of a logic and mathematical procedure whichtransforms chemical information encoded within a symbolicrepresentation of a molecule into a useful number or a resultof a standardized experiment . Those parameters were
(i) MLOGP: Moriguchi octanol-water partition coeffi-cient,
(ii) Balaban index (BI), Narumi topological index (NTI),total structure connectivity index (TSC), Wienerindex (WI): numerical parameters characterizingcompounds topology,
(iii) HOMO: highest occupied molecular orbital,(iv) LUMO: lowest unoccupied molecular orbital,(v) HOMO-LUMO gap (HL gap): the energy difference
between the HOMO and LUMO,
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(vi) dipole (dip): electric dipole moment,(vii) radius of gyration (ROG): the root mean square
distance of the entities parts from either its center ofgravity or a given axis,
(viii) molecular weight (MW) of compounds.
2.5. Antifungal Activity. Candida albicans ATCC 90028 mi-croorganisms were used to evaluate antifungal activity ofcompounds by minimal fungicidal concentration (MFC).MFC determination method was presented in .
According to the value of MFC objects were sorted intothree decision classes:
(i) class good: good antifungal properties: MFC 0.028mM/L,
(ii) classmedium:medium antifungal properties: 0.028