Antimicrobial Activity of a Series of ...

Folia Microbiol. 52 (1), 15–25 (2007)

http://www.biomed.cas.cz/mbu/folia/

Antimicrobial Activity of a Series of Thiosemicarbazones and Their ZnII and PdII Complexes İ. KIZILCIKLIa, Y.D. KURTa, B. AKKURTa, A.Y. GENELa, S. BIRTEKSÖZb, G. ÖTÜKb, B. ÜLKÜSEVENa aDepartment of Chemistry, Istanbul University, Avcılar, Istanbul, Turkey

e-mail [email protected] bPharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Beyazıd, Istanbul, Turkey

Received 5 June 2006

ABSTRACT. Thirty-four thiosemicarbazones and S-alkyl thiosemicarbazones, and some of their ZnII and PdII complexes were obtained and purified to investigate antimicrobial activity. MIC values of the compounds were determined by the disc diffusion method against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, Staphylococcus aureus, S. epidermidis, and Candida albicans. The thiosemicarbazones show antibacterial and antifungal effects in free ligand and metal-complex form. Picolinaldehyde-S-methyl- and -S-benzylthiosemicarbazones did not affect the tested microorganisms but their ZnII complexes showed selective activity. The antimicrobial activity is relatively high in Me2SO, but the antimicrobial potential is changed in a certain range with Me2SO, HCONMe2, EtOH and CHCl3.

Thiosemicarbazones and their metal complexes have a wide range of biological properties. Because of this, a large number of organic and metal-organic compounds derived from thiosemicarbazone have been the subject of most structural and medicinal studies. Some of the detected biological activities of the thiosemicarbazones are antibacterial (Gialdi et al. 1951; Rida et al. 1986; Cocco et al. 1990; Cardia et al. 2000; Kasuga et al. 2001; Rodriguez-Arguelles et al. 2005), antifungal (Offiong and Martelli 1993, 1994; Chohan et al. 2005), antiarthritic (Missbach et al. 1996), antimalarial (Walcourt et al. 2004), antiamebic (Bharti et al. 2003), antitumor (Ainscough et al. 1998; Sau et al. 2003) antiviral (Omar et al. 1984; Shipman et al. 1996; Heinisch and Tresselt 1977; Varadinova et al. 2001), and specially anti-HIV activity (Mishra et al. 2002; Genova et al. 2004; Bal et al. 2005). However, there is a limited number of studies on S-alkylthiosemicarbazones, in spite of their importance in selective biological activity. The biological features of S-alkylthiosemicarbazones have been reported (Amlacher 1985; Waisser et al. 2005a). Recently, some specific effects of the S-alkylthiosemicarbazones were described: a series of S-alkyl-picolinaldehyde thiosemicarbazones show best inhibitory values against Mycobacterium tuberculosis H37Rv ATCC 27294 and INH-R ATCC35822 (Cocco et al. 2002). S-Ethyland allylisothiosemicarbazones of 4-trifluoromethylbenzaldehyde have been suggested as antimycobacterial drugs against M. avium infections. In addition, their analogs were tested against 32 Mycobacterium avium, and their MIC values were determined to be lower than rifampicin and other reference drugs (De Logu et al. 2005). Antimycobacterial activity was also described in groups of aryl benzylsulfanyl tetrazoles and alkylindole thiones (Waisser et al. 2005b, 2006). Here we determined the antimicrobial activity of 28 S-alkyl esters, 6 thiosemicarbazones (Fig. 1) and 18 of their ZnII and PdII complexes against eight bacteria and one fungus by the disc diffusion method. The solvent effect of Me2SO, HCONMe2, EtOH and CHCl3 on antimicrobial activity of the compounds was investigated.

MATERIAL AND METHODS Chemicals and apparatus. All chemicals were of reagent grade. Analytical data were obtained with a Carlo Erba 1106 analyser (Tubitak, Turkey) and Varian Spectra AA 220/SS atomic absorption spectrometer. IR spectra were recorded in KBr pellets with a Mattson 1000 FT-infrared spectrometer. The 1H-NMR spectra were recorded on a Varian INOVA 500 MHz spectrometer. The molar conductivity was measured in 1 mmol/L solutions in Me2SO at 25 ± 1 °C using a WPA CMD750 conductometer. Synthesis of thiosemicarbazones. The thiosemicarbazones and S-alkylthiosemicarbazones Ia–VIIIg were prepared according to Yamazaki (1975). The compounds were recrystalized from EtOH–Et2O mixtures

16

İ. KIZILCIKLI et al.

Vol. 51

by TLC test until it checked the purity. The identity of the compounds was confirmed by melting point, elemental analysis, IR and 1H-NMR spectra.

cis

trans

Ar

R2

R1

Ia Ib Ic Id

2-hydroxy-1-naphthyl

phenyl

methyl ethyl propyl benzyl

IIa IIb IIc

1H-indol-2-one-3-yl

H phenyl

H benzyl H

III

3-indolyl

H

H

IVa IVb IVc IVd IVe IVf

2-pyridinyl

H

methyl ethyl benzyl picol-3-yl methyl ethyl

Va Vb

3-pyridinyl

phenyl

H

methyl ethyl

Ar

R2

R1

VIa VIb VIc VId VIe VIf VIg VIh

2-hydroxyphenyl

H

H methyl ethyl allyl benzyl methyl ethyl allyl

VIIa VIIb VIIc

thiophen-3-yl

VIIIa VIIIb VIIIc VIIId VIIIe VIIIf VIIIg

phenyl

phenyl

H

H benzyl

phenyl H

phenyl

methyl ethyl allyl benzyl methyl ethyl allyl

Fig. 1. Structure of thiosemicarbazones Ia–VIIIg.

Physicochemical characteristics of thiosemicarbazones exhibiting antimicrobial activity are given in Table I, spectral data in Table II. Synthesis of 1 : 1 ZnII complexes. The solution of the thiosemicarbazone (0.50 mmol) in 5 mL EtOH was added to a solution of ZnCl2 (0.50 mmol) in 5 mL EtOH and the reaction mixture was stirred for 2 h. The yellow precipitate was collected by filtration and was washed with 2 mL portions of both cold EtOH and Et2O, respectively. The final product was dried in vacuo over P2O5 for 1 d (Bourosh et al. 1987; Ülküseven 1995). Synthesis of 1 : 1 Pd3II complexes. The solution of thiosemicarbazone (0.50 mmol) in 10 mL EtOH was added to 5 mL of freshly prepared Li2[PdCl4] solution (0.5 mmol) and the reaction mixture was stirred for 2 h. The orange (or brown) precipitate was collected by filtration and washed with 5 mL of cold EtOH and 5 mL Et2O. The product was dried over P2O5 for 8 h in vacuo (Douglas et al. 1996). The ZnII complexes of Ia, IVa, IVc, IVe, VIa–VIc, and PdII complexes of Ia, Ib, IVa, IVb, IVd– IVf, and VIa–VId were isolated by the above procedures with small modifications; some metal complexes, such as IVb, IVf and Vb with ZnCl2, and IIc and IVc with PdCl2 could not be isolated with sufficient yield and purity for antimicrobial tests. For the metal complexes having antimicrobial activity the color, mp, yield, molar conductivity, and elemental analysis see Table III, for spectral data (FT-IR, 1H-NMR) see Table IV. Antimicrobial activity against Candida albicans ATCC 10231, Salmonella typhi, Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538, Klebsiella pneumoniae ATCC 4352, Staphylococcus epidermidis ATCC 12228, Proteus mirabilis ATCC 14153, Shigella flexneri and Pseudomonas aeruginosa ATCC 27853 were investigated by the disc diffusion method (NCCLS 2000a). Mueller–Hinton agar (Difco, Detroit) was used for all bacterial strains, RPMI-1640 medium (Sigma-Aldrich) for the yeast strain. The media were melted

2006

ANTIMICROBIAL ACTIVITY OF THIOSEMICARBAZONES AND THEIR Zn AND Pd COMPLEXES 17

at 100 °C and, after cooling to 50 °C, were poured (20 mL) into plates (∅ 90 mm). After being solidified in the plates, the surface of the media was dried at 37 °C. The inoculum was prepared using a 4–6-h broth culture of each bacterium and 1-d culture of yeast strain adjusted to a turbidity equivalent to a 0.5 McFarland standard. A sterile cotton swab was dipped into the inoculum and the surface of the Mueller–Hinton agar was inoculated by streaking the swab. The surface of the media was allowed to dry for 3–5 min at room temperature. Solutions of 10 mg/mL of the compound in Me2SO, HCONMe2, EtOH, or CHCl3 in impregnated paper discs were applied to the surface of inoculated plates. The Mueller–Hinton agar plates were incubated at 35 °C for 18–24 h, RPMI-1640 agar plates 35 °C for 46–50 h. The diameter of the inhibition zones on the plates was measured. Minimum inhibitory concentration (MIC) of the compounds was determined by microbroth dilutions technique using Mueller–Hinton broth for bacteria, RPMI-1640 medium for C. albicans (NCCLS 2000b,c). Serial 2-fold dilutions ranging from 5000 to 4.9 μg/mL were prepared in the media. The inoculum was prepared using a 4–6-h broth culture of each bacterium and 1-d culture of C. albicans adjusted to a turbidity equivalent of an 0.5 McFarland standard, diluted in broth media to give a final concentration of 5 × 105 CFU/mL for bacteria and 0.5 × 103 to 2.5 × 103 CFU/mL for C. albicans in the test tray; they were covered and placed in plastic bags to prevent evaporation. The plates were incubated at 35 °C for 18–20 and 46–50 h for bacteria and yeast strain, respectively. The MIC was defined as the lowest concentration of compound giving complete inhibition of visible growth. Cefuroxime, ceftazidime and clotrimazole were used as reference for bacteria and yeast. Also as control, antimicrobial effects of the solvents were determined. According to the values of the controls, the results were evaluated.

RESULTS AND DISCUSSION Physical properties of the compounds. The thiosemicarbazones and their S-alkyl esters are in yellow tones, only some benzyl esters (Id, VIe) are colorless crystals. The free esters of the thiosemicarbazones (i.e. not hydrohalide salts) are generally not stable in solid state (except IVe) and could be obtained only as oily viscous liquids. While the free esters, e.g., 2-pyridyl-S-methyl4-phenylthiosemicarbazone (IVe), are very soluble in common organic solvents, such as CH2Cl2, at room temperature their hydrohalide salts are poorly soluble. The hydrohalide salts are soluble in polar solvents (EtOH, HCONH2, Me2SO). The ZnII and PdII complexes are also soluble in the polar solvents. The interaction of the ligands with MCl2 in a 1 : 1 molar ratio in EtOH yielded stable solid complexes corresponding to the general formulas [M(L)Cl2] and [M(L)Cl] (M = Zn, Pd; L = ligand) (Kızılcıklı et al. 2001, 2004b).

18


Vol. 51

2006


20


Vol. 51

2006


The ZnII complexes are bright yellow while the PdII ones are brown. The molar conductivity of the metal complexes, Λ, of the ZnII complexes ranges from 20 to 35, the PdII ones have a relatively low Λ, viz. ≈10 S cm2 mol–1. Howewer, the S-picol-3-yl-2-pyridyl-thiosemicarbazone (IVd) complex with PdCl2 has a very low value of ≈2 S cm2 mol–1, and the complex is different from the viewpoint of structure compared with the others (see Fig. 3). Spectral data. In the IR spectra of the HI salts of the ligands, the bands in the 3350–3180 cm–1 region are assigned to ν (NH2) vibrations. The 4-phenyl derivatives have only one band at c. 3180–3210 cm–1, as expected. The complicated band system at 1660–1535 cm–1 may be attributed to δ(NH) deformation and ν (C=N) vibrations belonging to azomethine, thioamide, and the pyridine ring. For some of the pyridylthiosemicarbazones (IVa, IVe, Vb), it can be recorded in three separate bands, one of them having a shoulder. The streching bands ν (CH) at 2910 ± 20 cm–1 and ν (C–S) at 640–655 cm–1 are present. The ν(NH2) and ν (C=N) vibrations of the ZnII complexes can be monitored with negligible shifts compared to the ligands. However, there are many essential changes in the spectra of the PdII complexes. The ν (C=N) bands shift to lower or higher frequency by 10–35 cm–1. [Pd(IVe)Cl2] and [Pd(IVf)Cl2] give these vibration bands at 3350 and 3370 cm–1 while in the ligand spectra they are at 3270 and 3250 cm–1, respectively. The spectrum of the PdII complex with S-picol-3-yl derivative (IVd) contains only one band at 3275 cm–1 instead of a dual ν (NH2) band system. The 1H-NMR spectra of the thiosemicarbazones were found to be as expected. The amide protons of the ligands were monitored at 8.40–10.25 ppm. The pyridine and phenyl ring protons were observed at ≈8.90–7.80 and 8.25– 6.95 ppm, respectively. These peaks form a broad singlet or lie within a nonsplitting peak since they are in the same system because of conjugation. In the spectra of some thiosemicarbazones syn–anti and cis–trans isomerisms were clearly observed. Especially, the cis–trans isomerism of methyl and ethyl groups as to the double bond in the N2=C moiety can be distinguished in the spectra of S-allylthiosemicarbazone (VIh). The ratio of the cis and trans structures can be measured from the integral values of the isomer peaks at ≈40 : 60. However, the isomer peaks could not be recorded for the metal complexes. In the ZnII complexes, the shift of the proton changes by 0.2–0.5 ppm, the difference of the azomethine proton being generally more apparent. Both spectra indicate that the ligands are coordinated to the ZnII ion first through azomethine nitrogen. It can be suggested that the PdII ion chelates in a similar manner, only the differences in chemical shifts are too excessive due to the powerful coordination of the Pd ion. Therefore, the spectra of the PdII complexes have a remarkable chemical shift of the protons in comparison with the ligands, especially in the case of the protons which are neighboring to the ring nitrogen. Taking into consideration the structural data of the analogous complexes in the literature, it can be said that the primary coordination sites of the thiosemicarbazones (Ia–VIIIg) are azomethine nitrogen and pyridine ring or phenolic oxygen (Campbell 1975; Padhye et al. 1985). The 5- or 4-member chelate ring formation is a known phenomenon of the classical thiosemicarbazone ligands. Therefore we suggest the tentative structural formulas for these types of the ZnII and PdII complexes (Fig. 2). A different peak pattern was recorded in the 1H-NMR spectra of PdII complexes with S-picol-3-yl-thiosemicarbazone (IVd). The fundamental changes were observed in the shift of pyridine ring protons and integral value of amide protons. This value gives only one proton on the amide nitrogen. The strong band at 3275 cm–1 in the IR spectra (ν (NH) vibration) support the view of deprotonation of the NH2 group by coordination of Pd ion. Both the analytical and spectral data indicate a pair of 5-member chelate rings for the structure of [Pd(IVd)Cl] (Fig. 3). Antimicrobial activity. The MIC values against eight bacteria and one fungus and the solvent effect are given in Tables V and VI. Six S-alkyl thiosemicarb-


22

Vol. 51

azones indicate some biological activity, two inactive derivatives (2-pyridyl-S-methyl- and 2-pyridyl-S-benzylthiosemicarbazones, IVa and IVc) have become efficient to some microorganisms in the case of the ZnII complex (Table V).

left

right

M

L

M

L

Zn Pd

IVa; IVc; IVe IVa–IVc; IVe; IVf

Zn Pd

Ia; VIa; VIb Ia; Ib; VIa–VIc; VIIa

Fig. 2. The 5- and 4-membered chelates.

On the other hand, MIC of 2-pyridyl-S-methyl4-phenyl derivative (IVe) against S. aureus has increased from 4.9 to 19.5 and 9.8 mg/L in ZnII and PdII complexes, respectively. There is a similar conclusion also for 2-pyridyl-S-picol-3-yl-thiosemicarbazone (IVd), namely, if so the IVd ligand has an average effect against all used microorganisms, [Pd(IVd)Cl] is effective only against S. epidermidis and E. coli. In comparison with IVf and [Pd(IVf)Cl2], the antimicrobial activity of the thiosemicarbazone decreased in the form of the PdII complex.

Fig. 3. Suggested structural formula of [Pd(IVd)Cl].

Table V. MIC values of the compounds (mg/L) Microorganisma

Compound Sa

Se

IVe IVd IVf VId VIe VIIb

4.9 78 9.8 9.8 4.8 78

19.5 19.5 19.5 – – –

– 78 – – – –

– 78 – – – –

– 156 – – – –

– 39 – – – –

– 78 – – – –

312 78 – – – –

[Zn(IVa)Cl2] [Zn(IVc)Cl2] [Zn(IVe)Cl2]

– 78 19.5

– 39 19.5

– 156 62.5

– – –

– – –

– – –

156 – –

– – –

– – 312

[Pd(IVd)Cl] [Pd(IVe)Cl2] [Pd(IVf)Cl2]

– 9.8 9.8

78 19.5 19.5

62.5 – 312

– – –

– – –

– – –

– – –

– – –

– 15.6 312

Cefuroximeb Ceftazidime Clotrimazole

1.2 – –

9.8 – –

4.9 – –

– 4.9 –

– 2.4 –

2.4 – –

4.9 – –

– 2.4 –

aSa

Ec

Kp

Pa

Staphylococcus aureus (ATCC 6538) Se Staphylococcus epidermidis (ATCC 12228) Ec Escherichia coli (ATCC 8739) Kp Klebsiella pneumoniae (ATCC 4352) Pa Pseudomonas aeruginosa (ATCC 1539) bSodium salt. cMissbach et al. (1996) give the value of 3.12.

St Sf Pm Ca

St

Sf

Pm

Ca 19.5 19.5 4.9 – – –

– – 4.9c

Salmonella typhi Shigella flexneri Proteus mirabilis (ATCC 14153) Candida albicans (ATCC 10231)

The thiosemicarbazones and their metal complexes are usually effective on S. aureus, S. epidermidis, E. coli and C. albicans (Table V). The MIC values indicated that the pyridine ring containing deriva-

2006


tives (IVd–IVf) are more effective than the others. Especially, picolinaldehyde-S-picol-3-yl-thiosemicarbazone (IVd) having two pyridine rings shows an antimicrobial activity in a wide spectrum. Besides, all compounds except [Zn(IVa)Cl2] are effective against some microorganisms while ceftazidime and clotrimazole standards are not effecteve. Table VI. MIC values (mg/L) for IVd–IVf, VId and [Zn(IVe)Cl2] against some microorganisms in different solvents Microorganisma

Me2SO

HCONMe2

EtOH

CHCl3

IVd

Sa Se Kp Pa Sf Pm Ca

78 19.5 78 156 78 78 19.5

– 78 625 78 625 39 15.6

– 78 625 39 312 78 15.6

39 78 – – – 78 39

IVe

Sa Se Pm Ca

4.9 19.5 312 19.5

312 – – –

– 39 – –

62 78 – –

IVf

Sa Se Ca

9.8 19.5 4.9

78 – 39

39 – 39

39 – 39

Compound

VId

Sa

9.8

[Zn(IVe)Cl2]

Sa Se Ca

19.5 19.5 312

aSee footnote to Table V.

78

78

78 – 19.5

78 39 19.5

– (*)b (*)b (*)b

b(*) – insoluble.

Solvent effects of Me2SO, HCONMe2, EtOH and CHCl3 were studied with a limited number of an antimicrobial-activity-exibiting thiosemicarbazones (Table VI). The antimicrobial activity did not change in a wide range by all 4 solvents; however, the MIC values of some compounds (IVd–IVf, VIh) were determined between 4.9 and 625 mg/L. For S-picol-3-yl-thiosemicarbazone (IVd) the solvent effect is rather apparent. Compound IVd gave MIC values of 78, 625 and 312 mg/L against S. flexneri in Me2SO, HCONMe2 and EtOH, respectively, while 156, 78 and 39 mg/L against P. aeruginosa. Another remarkable result is that 2-pyridyl-S-methyl-4-phenyl-thiosemicarbazone (IVe) gives MIC values in the range of 19.5–78 against S. epidermidis in Me2SO, EtOH and CHCl3 but showed no activity in HCONMe2. The MIC value can be sensitive to the solvent. The MIC data have provided again a correlation between MIC value and solvent; of course, it is not right to generalize such result because various data were obtained for some thiosemicarbazones only. However, we show that the solvent effect on the MIC value can be quantitatively determined. This work was supported by the Research Fund of Istanbul University (project no. 1162/070998). REFERENCES AINSCOUGH E.W., BRODIE A.M., DENNY W.A., FINLAY G.J., RANFORD J.D.: Nitrogen, sulfur and oxygen donor adducts with copper(II) complexes of antitumor 2-formylpyridine thiosemicarbazone analogs: physicochemical and cytotoxic studies. J.Inorg.Biochem. 70, 175–185 (1998). AMLACHER R.: Route-dependent different relations between acute and subacute toxicity of the potential antiviral agent benzoxazolyl2-formyl-S-ethyl-isothiosemicarbazone in mice. Pharmazie 40, 132–133 (1985). BAL T.R., ANAND B., YOGEESWARI P., SRIRAM D.: Synthesis and evaluation of anti-HIV activity of isatin β-thiosemicarbazone derivatives. Bioorg.Med.Chem.Lett. 15, 4451–4455 (2005). BHARTI N., SHARMA S.S., NAQVI F., AZAM A.: New palladium(II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones: synthesis, spectral studies and in vitro anti-amoebic activity. Bioorg.Med.Chem. 11, 2923–2929 (2003). BOUROSH P.N., GERBELEU N.V., REVENKO M.D., SIMONOV Y.A., BELSKII V.K., BYROTOSU N.I.: Preparation and crystal structure of salicylaldehyde S-methyl-4-phenylthiosemicarbazone(H2L) and its copper complex [Cu(HL) H2O]NO3. Russ.J.Inorg.Chem. 32, 1446–1450 (1987). CAMPBELL M.J.H.: Transition metal complexes of thiosemicarbazide and thiosemicarbazones. Coord.Chem.Rev. 15, 279–287 (1975).

24


Vol. 51

CARDIA M.C., BEGALA M., DELOGU A., MACCIONI E., PLUMITALLO A.: Synthesis and antimicrobial activity of novel arylideneisothiosemicarbazones. Farmaco 55, 93–98 (2000). CHOHAN Z.H., PERVEZ H., KHAN K.M., SUPURAN C.T.: Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1´-diacetylferrocene-derived thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone. J.Enzyme Inhib.Med.Chem. 20, 81–88 (2005). COCCO M.T., CONGIU C., ONNIS V., PELLERANO M.L., DE LOGU A.: Synthesis and antimycobacterial activity of new S-alkylisothiosemicarbazone derivatives. Bioorg.Med.Chem. 10, 501–506 (2002). DE LOGU A., SADDI M., ONNIS V., SANNA C., CONGIU C., BORGNA R., COCCO M.T.: In vitro antimycobacterial activity of newly synthesized S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium. Internat.J.Antimicrob.Agents 26, 28–32 (2005). DOUGLAS X.W., MICHELLE M.G., GORDON A.B., PAUL D.B.: Structures and spectral properties of palladium(II) complexes of 2-acetylpyridine N(4)-dimethylthiosemicarbazone. Polyhedron 15, 2587–2596 (1996). GENOVA P., VARADINOVA T., MATESANZ A.I., MARINOVA D., SOUZA P.: Toxic effects of bis(thiosemicarbazone) compounds and its palladium(II) complexes on herpes simplex virus growth. Toxicol.Appl.Pharmacol. 197, 107–112 (2004). GIALDI F., PONCI R.: Antibacterial activity of quinoline derivatives. V. Preparation and in vitro antibacterial activity of 6,6´-diquinolylsulfone and various thiosemicarbazones of quinoline aldehydes. Farmaco 6, 332–336 (1951). HEINISCH L., TRESSELT D.: Complex formation of antiviral isatin-3-isothiosemicarbazones and thiocarbonylhydrazones using transition-group metals. Pharmazie 32, 582–586 (1977). KASUGA N.C., SEKINO K., KOUMO C., SHIMADA N., ISHIKAWA M., NOMIYA K.: Synthesis, structural characterization and antimicrobial activities of 4- and 6-coordinated nickel(II) complexes with three thiosemicarbazones and semicarbazone ligands. J.Inorg. Biochem. 84, 55–65 (2001). KIZILCIKLI İ., ÜLKÜSEVEN B., DASDEMIR Y.: Synthesis and structural analysis of oligo-element complexes of some thiosemicarbazoneS-alkyl esters derived from 2- and 3-pyridinecarboxaldehydes. The Research Fund of the University of İstanbul, project no. 1162/070998 (2001). KIZILCIKLI İ., AKKURT B., ÜLKÜSEVEN B.: Potentiometric investigation of FeIII, NiII and CuII complexes of some isatin and thiophene isothiosemicarbazones. Rev.Inorg.Chem. 24, 31–38 (2004a). KIZILCIKLI İ., ÜLKÜSEVEN B., DASDEMIR Y., AKKURT B.: ZnII and PdII complexes of thiosemicarbazone-S-alkyl esters derived from 2/3-formylpyridine. Synth.React.Inorg.Met.-Org.Chem. 34, 653–665 (2004b). MISHRA V., PANDEYA S.N., PANNECOUQUE C., WITVROUW M., DE CLERCQ E.: Anti-HIV activity of thiosemicarbazone and semicarbazone derivatives of (+/–)-3-menthone. Arch.Pharm. 335, 183–186 (2002). MISSBACH M., JAGHER B., SIGG I., NAYERI S., CARLBERG C., WIESENBERG I.: Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor α with potent antiarthritic activity. J.Biol.Chem. 271, 13515–13522 (1996). NCCLS (National Committee for Clinical Laboratory Standards): Performance Standards for Antimicrobial Disk Susceptibility Tests, 7th ed. Approved Standard M2-A7. NCCLS, Wayne (USA) 2000a. NCCLS (National Committee for Clinical Laboratory Standards): Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, 5th ed. Approved Standard M7-A5. NCCLS, Wayne (USA) 2000b. NCCLS (National Committee for Clinical Laboratory Standards): Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. Approved Standard M27-A. NCCLS, Wayne (USA) 2000c. OFFIONG O.E., MARTELLI S.: Synthesis, antibacterial and antifungal activity of metal(II) complexes of 2-acetylpyridine thiosemicarbazones. Farmaco 48, 777–793 (1993). OFFIONG O.E., MARTELLI S.: Antibacterial activity of metal complexes of benzil and benzoin thiosemicarbazones. Farmaco 49, 513– 518 (1994). OMAR A.M., ESHBA N.H., SALAMA H.M.: Syntheses of some substituted isatin-β-thiosemicarbazones and isatin-β-hydrazonothiazoline derivatives as potential antiviral and antimicrobial agents. Arch.Pharm. 317, 701–709 (1984). PADHYE S., KAUFFMAN G.B.: Transition metal complexes of semicarbazones and thiosemicarbazones. Coord.Chem.Rev. 63, 127–160 (1985). RIDA S.M., LABOUTA I.M., SALAMA H.M., GHANY Y.S., EL-GHAZZAUI E., COCCO M.T., PLUMITALLO A., SCHIVO M.L., DE LOGU A.: Antimicrobial activity of some isothiosemicarbazones. Farmaco 45, 1101–1109 (1990). RODRIGUEZ-ARGUELLES M.C., LOPEZ-SILVA E.C., SANMARTIN J., PELAGATTI P., ZANI F.: Copper complexes of imidazole-2-, pyrrole2- and indol-3-carbaldehyde thiosemicarbazones. Inhibitory activity against fungi and bacteria. J.Inorg.Biochem. 99, 2231– 2239 (2005). SAU D.K., BUTCHER R.J., CHAUDHURI S., SAHA N.: Spectroscopic, structural and antibacterial properties of copper(II) complexes with bio-relevant 5-methyl-3-formylpyrazole N(4)-benzyl-N(4)-methylthiosemicarbazone. Mol.Cell Biochem. 253, 21–29 (2003). SHIPMAN J., SMITH S.H., DRACH J.C., KLAYMAN D.L.: Thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds as inhibitors of in vitro and in a cutaneous herpes guinea pig model. Antiviral Res. 6, 197–204 (1986). ÜLKÜSEVEN B.: Studies of S-ethylthiosemicarbazones with CuII, ZnII, CdII, HgII chloride salts. Synth.React.Inorg.Met.-Org.Chem. 25, 1549–1560 (1995). VARADINOVA T., KOVALA-DEMERTZI D., RUPELIEVA M., DEMERTZIS M., GENOVA P.: Antiviral activity of platinum(II) and palladium(II) complexes of pyridine-2-carbaldehyde thiosemicarbazone. Acta Virol. 45, 87–94 (2001). WAISSER K., HEINISCH L., ŠLOSÁREK M., JANOTA J.: New antimycobacterial S-alkylisothiosemicarbazones. Folia Microbiol. 50, 479– 482 (2005a). WAISSERK., ADAMEC J., DOLEŽAL R., KAUSTOVÁ J.: 1-Aryl-5-benzylsulfanyltetrazoles, a new group of antimycobacterial compounds against potentially pathogenic strains. Folia Microbiol. 50, 195–197 (2005b).

2006


WAISSER K., HEINISCH L., ŠLOSÁREK M., JANOTA J.: New antimycobacterial 2,3-dihydro-1-alkylindole-2-thiones. Folia Microbiol. 51, 25–26 (2006). WALCOURT A., LOYEVSKY M., LOVEJOY D.B., GORDEUK V.R., RICHARDSON D.R.: Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites. Internat.J.Biochem.Cell Biol. 36, 401–407 (2004). YAMAZAKI C.: The structure of isothiosemicarbazones. Can.J.Chem. 53, 610–615 (1975). YOMPOLSKAYA M.A., GERBELEU N.V., SIMONOV Y.A., BEĽSKII V.K., DVORKIN A.A.: Template synthesis of mu-oxo dimers of iron(III) and crystal and molecular structure of μ-oxo-bis[S-methyl-N 1,N 4-di(salicylidene) isothiosemicarbazidato-O,N 1,N 4]-iron(III) dihydrate. Zh.Neorg.Khim. 28, 1744–1754 (1983).