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Investigation of Antimicrobial, Antibiofilm, and Cytotoxic Effects of Straight-Chained Sulfanyl Members of Arylamino-1,4-naphthoquinones as Potential Antimicrobial Agents.


Discovering the potential of naphthoquinone compounds as antimicrobial agents increased the efforts towards synthesis new molecules and investigation of their antimicrobial properties by scientists (1, 2). Structure-activity relationship studies performed to determine structural features or functional groups of the naphthoquinone derivatives that increase or decrease antimicrobial activity pointed out that the incorporation of substituted aromatic ring and sulphur (S) atom in the quinone skeleton was an important factor for enhancing the biological activities (3). The increase in the number of studies on this subject is not surprising. In this context, it is no surprise that recent studies contain these activity increasing substituents (4, 5). Recently Errante et al. reported that some thio derivatives of naphthoquinones exhibited better activities than amphotericine B against some fungi (6). In a previous study, phenylamino derivatives of naphthoquinone that also bear straight chain thiol groups in the structure as substituents were obtained. Infrared, NMR ([.sup.1]H, [.sup.13]C), and mass spectrometry were first used by Bayrak to identify their structures as original compounds (Figure 1) (7).

In the present study, we evaluated the potential antimicrobial, antibiofilm, and bactericidal efficacies of previously synthesized (7) thio derivatives of phenylamino-naphthoquinones against several pathogen microorganisms. Moreover, the cytotoxic activity of compound 5a (which has the strongest antimicrobial activity in diverse cancer cell lines in comparison to non-cancerous cell lines) was examined.



The proposed routine quality control strains used in order to screen test performance with synthesized compounds in test panels are shown in Table 1. Staphylococcus aureus (ATCC 25923) was included in the experiment as a reference strain to confirm the biofilm forming bacteria to ensure antibiofilm activity of the compound. Inoculums of bacteria and yeasts were prepared with overnight cultures to cultivate a concentration of 1x[10.sup.8] colony forming units (CFU/mL) and 1x[10.sup.7] CFU/mL, respectively.


Tryptic soy broth (TSB- Difco Laboratories) plus 1% glucose was used for the biofilm production and antibiofilm activities assays. Mueller-Hinton broth (MHB, Oxoid) was used to identify the minimum inhibitory concentration (MIC) and time-kill curve; and Tryptic Soy agar (TSA, Difco Laboratories) was used for vital growth colony counts.

Antimicrobial Activity Assessment

Minimum Inhibitory Concentration Assay

This assay comprises of the determination of the synthesized compounds' spectrum of antimicrobial susceptibility in compliance with the resistance of studied Gram positive/negative bacteria and yeasts by the CLSI broth microdilution reference method (8, 9). The MIC was defined as the lowest concentration of the molecules causing complete inhibition in visible growth. The antimicrobial effect of the solvents was determined as a control and the test results were evaluated accordingly.

The conclusion from the antimicrobial activity tests prompted our research to investigate in vitro antimicrobial activities of compound 5a contrary to 20 clinically obtained strains of Staphylococcus aureus by the CLSI broth microdilution reference method (8).

Antibiofilm Activity Assesment

The initial biofilm attachment assay and inhibition of biofilm formation tests were performed by using a slightly modified version of the method by Mataraci et al. (10) that was previously explained. 1/10 x MICs of the compound 5a were appended to the 24 h biofilm and the plates were incubated for 1, 2 and 4 h for S. aureus ATCC 25923 (biofilm forming bacteria) at 37[degrees]C; molecules at 1x, 1/10x and 1/100 x MIC concentrations were appended to the 24 h biofilm and the wells were incubated for 24 h at 37 [degrees]C, respectively. Six wells were used for the tested compound. Sterile TSB-glucose was used for the positive controls. Then the plates were washed with PBS and evaluated at OD595 nm (BioTek EON Microplate Reader).

Determination of Bactericidal Effects by Time-Kill Curves

Time-kill curve analyses were performed by culturing S. aureus ATCC 29213 in MHB medium, in the presence of 5a at 1 x MIC. An assessment of the dynamic bactericidal activity of compound 5a was made with the time-kill curve method by testing at 1x times the MIC against S. aureus ATCC 29213 as described previously. Solvent containing the control was included in the test for the tested strain. The inoculum was quantified spectrophotometrically and added to the flasks. The antimicrobial amount was checked by the inhibition of viable colony growth at the site of the initial inoculum in accordance with NCCLS recommendations (11). Bactericidal activity was described as a decrease of [greater than or equal to] 3 [log.sub.10] CFU/mL from the initial inoculum at 24 h.

Cell Cultures

Three non-cancer cell lines were used in this study: Mouse embryonic fibroblast (BALB/3T3), human umbilical vein endothelial cell (HUVEC), and human keratinocyte (HaCaT). The three cancer cell lines used were human hepatocelular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), and human prostate cancer cell (PC-3). All cells were grown with DMEM medium containing 10% fetal bovine serum and 1% antibiotic-antimicotic solution in a 37 [degrees]C, 5% C[O.sub.2] humidified incubator. The cells were passaged routinely at a confluence of 90% by trypsinization.

Cell Treatments and Cytotoxicity Assay

For the cytotoxicity assay, the cells were seeded in 96 well plates 1x[10.sup.4] cells/well and incubated overnight for cell attachment. Subsequently, the media were replaced with fresh media and the cells were treated with compound final concentrations 100-6.25 [micro]g/mL and vehicle control 1% DMSO for 24 h at 37 [degrees]C. After 24 hours, cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The final volume of the 5 mg/mL MTT reagent was added to the wells and the plates were incubated in the dark for 3 h.

The media was then removed and the formazan precipitates were dissolved in 100 [micro]L DMSO. Optical density was measured using a microplate reader (Biotek Instruments, Inc., Vermont, USA) at 590 nm. Cell viability was expressed as a percentage of the absorbance recorded for vehicle control.

Statistical Analysis

All tests were performed in three independent assays. One-way ANOVA, Bonferroni's multiple comparison test was used to compare the differences between the control and compound-treated biofilms and time-kill kinetics. A p value < 0.001 was considered as statistically significant.



In this study, we used six molecules (2-(4-(trifluoromethyl) phenylamino)-3-(propylthio)naphthalene-1,4-dione (5a), 2-(4-(trifluoromethyl)phenylamino)-3-(pentylthio)naphthalene-1,4-dione (5b), 2-(4-(trifluoromethyl)phenylamino)-3-(nonylthio) naphthalene-1,4-dione (5c), 2-(3-(trifluoromethyl)phenylamino)-3-(propylthio)naphthalene-1,4-dione (5d), 2-(3-(trifluoromethyl) phenylamino)-3-(pentylthio)naphthalene-1,4-dione (5e), 2-(3-(trifluoromethyl)phenylamino)-3-(nonylthio)naphthalene-1,4-dione (5f) ) that had been previously synthesized by Bayrak (7). Bayrak reported that the thiol derivatives of phenylamino-1,4-naphthoquinones (5a-f) were obtained by a substitution reaction with phenylamino-chloro-1,4-naphthoquinone derivatives (3a-b) that synthesized by the chemical reaction of 2,3-dichloro-1,4-naphtoquinone with trifluoro substituted phenyl amines and the appropriate straight-chained thiol in dichloromethane were mixed at room temperature by applying [Et.sub.3]N (7). The reactions of 2-(4-(trifluoromethyl)phenylamino)-3-chloronaphthalene-1,4-dione (3a) and 2-(3-(trifluoromethyl) phenylamino)-3-chloronaphthalene-1,4-dione (3b) with aliphatic thiol compounds (propane, pentane, and nonane thiol) proceeded via the substitution of a chlorine atom with a sulfur atom to form phenylamino-1,4-naphthoquinones with straight chain thio group (5a-f). The structures of 5a-f were also clarified by IR, [.sup.1]H NMR, [.sup.13]C NMR, and MS data (Figure 1).

Antimicrobial Activity

The in vitro antimicrobial activity of six thio phenylamino-1,4-naphthoquinone derivatives (5a-f) against three Gram-positive bacteria, four Gram-negative bacteria, and three fungi by the microbroth dilutions technique using the CLSI recommendations (8, 9).

The antimicrobial experiment results of all the six sulfanyl derivatives of phenylamino-1,4-naphthoquinone (5a-f) are given in Table 2. The test-cultures E. coli, P. mirabilis, and K. pneumoniae appeared to be resistant to the all synthesized compounds. None of the studied molecules showed any antibacterial activity against the Gram-negative bacteria except for 5f. Concerning the antibacterial activity, the Gram-positive bacteria were more susceptible to the sulfanyl derivatives of phenylamino-1,4-naphthoquinone than the Gram-negative ones. Generally, the findings showed that some compounds displayed varying effects on the growth of the tested Gram-positive bacterial strains. The results showed that all thio-phenylamino-1,4-naphthoquinone derivatives exhibited antimicrobial activity against S. aureus. 5a and 5b showed good activity against 5. aureus with an MIC value of 1.22 and 19.53 [micro]g/mL, respectively. Notably, 5a had the same inhibitory activity against S. aureus as that of Cefuroxime-Na (MIC = 1.22 [micro]g/mL). An evaluation of the antifungal activity of the thio- phenylamino-1,4-naphthoquinone derivatives exhibited no antifungal activity against C. albicans, C. parapsilosis, and C. tropicalis except 5d. The 5d was active analog against C. tropicalis (MIC = 312.5 [micro]g/mL) (Table 2). According to our results, 5a was found active against the standard S. aureus, so we investigated the potential antimicrobial activity of this compound against 20 clinically obtained Staphyloccocus aureus (Table 3). Susceptibility testing demonstrated thatthe MIC ranges for 5a were 1250- >2500 ug/mL, for these clinically obtained strains.

Antibiofilm Activities

Because of the its potent activity, only 5a was used in the antibiofilm activities assays. When we carried out these tests, the agent inhibited the biofilm attachment according to time, and it showed an important inhibitor activity against biofilm formation at 24 h depending on concentration (Figure 2).

Time-kill Kinetics

Time-kill kinetic studies showed that the naphthoquinone compounds used in this study displayed concentration-dependent bactericidal activity. When 5a was used at 1 x MIC, bactericidal activity was not seen for the studied strain S. aureus ATCC 29213 at 24 h (Figure 3). However, in our study 5a only showed approximately 2 [log.sub.10] reduction in bacterial cell count at the 1 x MIC concentration used.

Cytotoxicity Assay

The cytotoxicity of 5a was screened in three different non-cancer cell lines, mouse embryonic fibroblast (BALB/3T3), human umbilical vein endothelial cell (HUVEC), and human keratinocyte (HaCaT), together with three cancer cell lines, human hepatocellular carcinoma (HepG2), human neuroblastoma (SH-SY5Y), and human prostate cancer cell (PC-3). In all cell lines 5a decreased cell proliferation significantly after 24 h. The most significant effect was seen in the HepG2 cell line with an [IC.sub.50] value of 21.96 [micro]g/mL. 5a showed a similar cytotoxic effect in the SH-SY5Y and PC-3 cells with [IC.sub.50] values of 31.94 [micro]g/mL and 31.95 [micro]g/mL, respectively (Figure 4). 5a had [IC.sub.50] values of 60.72 [micro]g/mL, 5727 [micro]g/mL, and 38.8 [micro]g/mL against non-cancer cells, HaCaT, 3T3, and HUVEC cells respectively (Figure 5), implies that higher concentrations of compound exhibit toxicity to non-cancer cells.


The increase and spread of antimicrobial resistance among the various microorganisms is now one of the world's major health problems. Antibiotic resistance is increasing both in the community and in hospitals, multidrug resistant (MDR) and even-pan resistant strains (resistant to all common antibiotic groups for therapeutic use), which lead to failure of antibiotic treatment, increased mortality and morbidity and have a huge increase on the cost of medical treatment and prevention of bacterial infectious diseases (12, 13). For these reasons, researchers have produced many synthetic or semi-synthetic molecules as candidates for new and benefical drugs (13-15). The discovery of new antibacterial agents or multidrug agents for reversing is critical as we may not have any effective medicines to treat bacterial infections caused by the emerging superbugs that are resistant to the majority of clinically available antibiotics (16).

In our present study, the in vitro actimicrobial activities of known phenylamino derivatives of naphthoquinone having straight chain thiol groups were evaluated and two molecules (5a and 5b) were found to have a potent antibacterial efficacy against S.aureus human-pathogenic strains and causes not only community acquired but also immortal nosocomial infections (10).

The communities of microorganisms attached to a surface were termed 'biofilm'. Bacteria within the biofilm require a 100 to 1000 times greater antibiotic concentration to achieve destruction versus planktonic bacteria. Standard intravenous therapy does not reach a high enough concentration to reduce the bacterial burden within the biofilm. It is a fact that this is the case for up to 60% of the infections which are usually associated with microorganisms that have settled in the microbial biofilms. Not all antimicrobial agents are the same in terms of biofilm eradication. The agent's mechanism of action, its interaction with the biofilm matrix and the effect of biofilm related parameters such as oxygen concentration, biofilm and growth rate should be considered (17-19). To this end, we researched the inhibition of surface bacterial adhesion and the inhibition of biofilm production by MIC or sub-MIC values of the 5a compound. 5a significantly inhibited the attachment of bacteria at 1/10 x MIC in 1-4 h and 24 h biofilm formation up to 40%, in particular at 1 x MIC (p <0.001). Although the inhibition of mature biofilm is very difficult, the inhibition of biofilm formation seems to be more applicable in early critical stages.

Although 5a has limited bactericidal activity against S. aureus at 1 x MIC, it could be considered for future studies since its combination with antibiotics as an adjuvant could cause synergism, thus lowering 5a's potential toxic effects and preventing the development of resistance. Moreover, comparing the cytotoxic effect of the compound on non-cancer and cancer cell lines, we noticed that 5a showed higher toxicity to cancer cell lines. Human hepatocellular cancer HepG2 cells in particular were the most effected cells. This result may suggest potential anticancer use against human hepatocellular cancer.

HaCaT cells are immortalized human keratinocytes and it is a useful model for studying dermal toxicity. 5a showed the least toxicity to the HaCaT cells and [IC.sub.50] value was over 60 [micro]g/mL. Also, increasing doses of the compound did not cause more cytotoxic effect in the HaCaT cells. Additionally, the compound showed a 2-fold higher [IC.sub.50] value to the mouse embryonic fibroblast BALB/3T3 cells than the cancer cells. These results may indicate potential antibacterial dermal use of the compound in low concentrations without causing significant dermal toxicity. Follow-up research is essential to understand the compound's mechanism of action and define detailed the activity-structure relationship.


With respect to the antimicrobial, anticancer, and cytotoxic activities of the phenylamino derivatives of naphthoquinone that contain straight chain thiol groups in the structure as substituents which had been previously synthesized, further studies to establish their pharmacological properties would be helpful to define their functionality as antimicrobial or anticancer agents.

Peer-review: Externally peer-reviewed.

Author Contributions: Conception/Design of study: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.; Data Acquisition: E.M.K., A.T.J., N.B., B.O.C., B.A., H.Y.; Data Analysis/Interpretation: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.; Drafting Manuscript: B.O.C., B.A., M.Y., B.O.C., B.A., M.Y.; Critical Revision of Manuscript: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.; Final Approval and Accountability: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.; Technical or Material Support: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.; Supervision: E.M.K., A.T.J., N.B., B.O.C., B.A., M.Y., A.F.T., H.Y.

Conflict of Interest: The authors declare that they have no conflicts of interest.

Financial Disclosure: There are no funders to report for this submission.


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Emel Mataraci Kara (1) (iD), Ayse Tarbin Jannuzzi (2) (iD), Nilufer Bayrak (3) (iD), Hatice Yildirim (3) (iD), Mahmut Yildiz (4) (iD), Amac Fatih Tuyun (5) (iD), Buket Alpertunga (2) (iD), Berna Ozbek Celik (1) (iD)

(1) Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Istanbul, Turkey

(2) Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Istanbul, Turkey

(3) Istanbul University-Cerrahpasa, Engineering Faculty, Chemistry Department, Istanbul, Turkey

(4) Gebze Technical University, Faculty of Science, Department of Chemistry, Kocaeli, Turkey

(5) Istanbul University-Cerrahpasa, Engineering Faculty, Engineering Sciences Department, Istanbul, Turkey

ORCID IDs of the authors: E.M.K. 0000-0003-4541-1893; A.TJ. 0000-0003-0578-6893; N.B. 0000-0002-0777-4012; H.Y. 0000-0003-3988-6120; M.Y. 0000-0001-6317-5738; A.F.T. 0000-0001-5698-1109; B.A. 0000-0001-6043-7560; B.O.C. 0000-0001-8909-8398

Please cite this article as: Mataraci Kara E, Jannuzzi AT, Bayrak N, Yildirim H, Yildiz M, Tuyun AF, Alpertunga B, Ozbek Celik B. Investigation of Antimicrobial, Antibioflm, and Cytotoxic Efects of Straight-Chained Sulfanyl Members of Arylamino-1,4-naphthoquinones As Potential Antimicrobial Agents. Eur J Biol 2019; 78(2): 117-123. DOI: 10.26650/EurJBiol.2019.0017

Address for Correspondence: Emel Mataraci Kara


Submitted: 23.07.2019

Revision Requested: 19.08.2019

Last Revision Received: 16.10.2019

Accepted: 18.10.2019

DOI: 10.26650/EurJBiol.2019.0017
Table 1. The proposed routine quality control strains used to screen
test performance with synthesized compounds in test panels.

Organisms                   Culture Collection Numbers

Escherichia coli            ATCC 25922
Staphylococcus aureus       ATCC 29213
Staphylococcus epidermidis  ATCC 12228
Enterococcus faecalis       ATCC 29212
Pseudomonas aeruginosa      ATCC 27853
Proteus mirabilis           ATCC 14153
Klebsiella pneumoniae       ATCC 4352
Candida albicans            ATCC 10231
Candida parapsilosis        ATCC 22019
Candida tropicalis          ATCC 750

ATCC: American Type Culture Collection, 12301, Parklawn Drive,
Rockville, MD 20852, USA.

Table 2. In vitro antimicrobial activity results of
thio-phenylamino-1,4-naphthoquinone derivatives (5a-f).

                Gram-negative Bacteria (MIC, [micro]g/mL)
ID              aeruginosa   E. coli        K. pneumoniae  P. mirabilis

5e              -            -              -              -
5f              625          -              -              -
5b              -            -              -              -
5c              -            -              -              -
5d              -            -              -              -
5a              -            -              -              -
Reference         2.4        4.9            4.9            2.4
antimicrobials  Ceftazidime  Cefuroxime-Na  Cefuroxime-Na  Cefuroxime-Na

                Gram-positive Bacteria (MIC, [micro]g/mL)
ID              S. aureus      epidermidis  E. faecalis

5e               625           1250         -
5f              1250           1250         -
5b                19.53        1250         -
5c              1250           -            -
5d               312,5         -            -
5a                 1.22        1250         625
Reference          1.2            9.8       128
antimicrobials  Cefuroxime-Na  Cefuroxime   Amikacin

                Yeast (MIC, [micro]g/mL)
ID              C. albicans   C. parapsilosis  C. tropicalis

5e              -             -                -
5f              -             -                -
5b              -             -                -
5c              -             -                -
5d              -             -                312.5
5a              -             -                -
Reference       4.9           0.5                1
antimicrobials  Clotrimazole  Amphotericin B   Amphotericin B
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Author:Kara, Emel Mataraci; Jannuzzi, Ayse Tarbin; Bayrak, Nilufer; Yildirim, Hatice; Yildiz, Mahmut; Tuyun
Publication:IUFS Journal of Biology
Date:Dec 1, 2019
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