Synthesis and antimicrobial evaluation of new 3-alkyl/aryl-2-[((α, α-diphenyl-α-hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinones

Article abstract of DOI:10.1007/s12272-010-2221-y

New 4-thiazolidinone derivatives of benzilic acid (α,α- diphenyl-α-hydroxyacetic acid) have been synthesized and evaluated for antibacterial and antifungal activities. The reaction of 1- (α,α- diphenyl-α-hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate gave 3-alkyl/aryl-2-[((α,α-diphenyl-α- hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinone derivatives. Their antibacterial and antifungal activities were evaluated against S. aureus ATCC 29213, P. aeruginosa ATCC 27853, E. coli ATCC 25922, C. albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, T. mentagrophytes var. erinacei NCPF 375, M. gypseum NCPF 580 and T. tonsurans NCPF 245. 3e, 3f, 3g and 3h showed the highest antibacterial activity. Particularly 3a and 3e showed the highest antifungal activities against C. parapsilosis ATCC 22019, T. tonsurans NCPF 245 and M. gypseum NCPF 580.

Full text of DOI:10.1007/s12272-010-2221-y

Arch Pharm Res Vol 33, No 1, 17-24, 2010
DOI 10.1007/s12272-010-2221-y
Synthesis and Antimicrobial Evaluation of New 3-Alkyl/aryl-2-[((α,α-
diphenyl-α-hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinones
Nuray Ulusoy Güzeldemirci1, Eser Ilhan1, Ömer Küçükbasmaci2, and Dilek Satana3
2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey, Department of
3
Microbiology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey, and Department of Microbiology,
Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
(Received August 2, 2009/Revised October 14, 2009/Accepted October 20, 2009)
New 4-thiazolidinone derivatives of benzilic acid (
been synthesized and evaluated for antibacterial and antifungal activities. The reaction of 1-
-diphenyl- -hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate
gave 3-alkyl/aryl-2-[(( -diphenyl- -hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinone
α,α-diphenyl-α-hydroxyacetic acid) have
(α
,
α
α
α
,
α
α
derivatives. Their antibacterial and antifungal activities were evaluated against S. aureus
ATCC 29213, P. aeruginosa ATCC 27853, E. coli ATCC 25922, C. albicans ATCC 10231, C.
parapsilosis ATCC 22019, C. krusei ATCC 6258, T. mentagrophytes var. erinacei NCPF 375,
M. gypseum NCPF 580 and T. tonsurans NCPF 245. 3e, 3f, 3g and 3h showed the highest
antibacterial activity. Particularly 3a and 3e showed the highest antifungal activities against
C. parapsilosis ATCC 22019, T. tonsurans NCPF 245 and M. gypseum NCPF 580.
Key words: Benzilic acid, 4-Thiazolidinone, Antibacterial activity, Antifungal activity
activities such as antibacterial (Mishra et al., 2007;
Aquino et al., 2008; Bondock et al., 2007; Shah et al.,
INTRODUCTION
The extensive use of antibiotics has led to the ap- 2007; Kumar et al., 2006; Rida et al., 2005), antifungal
pearance of multi-drug resistant microbial pathogens (Özkirimli et al., 2008; Kaplancikli et al., 2008;
(Frère, 1995). This highlights the incessant need for Siddiqui et al., 2003), antituberculosis (Küçükgüzel et
the development of new classes of antimicrobial al., 2002; Küçükgüzel et al., 2006; Karali et al., 2007),
agents and alteration of known drugs in such way anti-HIV (Rawal et al., 2008; Balzarini et al., 2007;
that would allow them to retain their physiological Rao et al., 2004; Rao et al., 2004; Rao et al., 2003),
action, but reducing their resistance to the pathogen. anticancer (Ali et al., 2007), anticonvulsant (Archana
The design of novel chemotherapeutic agents is et al., 2002; Amin et al., 2008; Gürsoy et al., 2005),
particularly beneficial due to their dissimilar mode of anti-inflammatory (Kumar et al., 2009; Bhati et al.,
action which can avoid cross resistance to known 2008; Goel et al., 1999) and antihistaminic (Diurno et
drugs.
al., 1999) activities. On the other hand,
-hydroxy)acetyl moiety are also associated with
α,α-diphenyl-
There has been considerable interest in the
α
chemistry of 4-thiazolidinone ring systems, which is a various biological properties including antimicrobial
core structure in various synthetic pharmaceuticals activity (Ilhan and Ergenç, 1992; Ilhan et al., 1994).
displaying a broad spectrum of biological activities As a continuation of our previous studies on 4-thiazo-
(Vigorita et al., 2001; Kavitha et al., 2006). 4-Thiazoli- lidinone derivatives (Ulusoy et al., 2002; Çapan et al.,
dinone derivatives are known to exhibit diverse bio- 1999; Ulusoy et al., 1998; Ulusoy et al., 1997; Ulusoy
et al., 1996; Çapan et al., 1996) and on
-hydroxy)acetyl moiety (Ilhan et al., 1996), we syn-
thesized new 3-alkyl/aryl-2-[(( -diphenyl- -hydroxy)
acetyl)hydrazono]-5-methyl-4-thiazolidinones in order
to screen them for antibacterial and antifungal acti-
vities. Structural elucidation of these compounds was
α,α-diphenyl-
α
Correspondence to: Nuray Ulusoy Güzeldemirci, Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul Uni-
versity, 34116, Beyazit/istanbul/Turkey
Tel: 90-212-455 5778, Fax: 90-212-440 0252
E-mail: nulusoy@istanbul.edu.tr
α,α
α
17

18
N. U. Güzeldemirci et al.
1
performed by IR, H-NMR, mass spectroscopy and 7.28-7.41 (10H, m, Ar-H); 10.10 (1H, s, NH); EIMS (70
elemental analysis.
eV) m/z (%): 411 (M+, 4), 393 (98), 364 (37), 228 (16),
208 (37), 201 (42), 183 (100, base peak), 165 (34), 131
(22), 105 (47), 77 (14). Anal. Calcd for C22H25N3O3S: C,
64.21; H, 6.12; N, 10.21. Found: C, 64.12; H, 6.37; N,
MATERIALS AND METHODS
Melting points were estimated with a Büchi 530 9.56.
capillary melting point apparatus in open capillary
tubes and are uncorrected. IR spectra were recorded 3-(2-Phenylethyl)-2-[((
α,α-diphenyl-α-hydroxy)
(in KBr) on a Perkin Elmer 1600 FT Infrared spectro- acetyl)hydrazono]-5-methyl-4-thiazolidinone (3c)
photometer. 1H-NMR spectra were recorded on Bruker Yield 93%; m.p. 155-156oC; IR (KBr): (cm-1) 3500
AC 200 (200 MHz) spectrophotometer and Bruker (OH), 3383 (NH), 1721, 1650 (C=O); H-NMR (400
DPX 400 (400 MHz) spectrophotometer using tetra- MHz, DMSO-d6): (ppm) 1.51 (3H, d, = 7.1 Hz,
methylsilane as internal standard. EI/MS were re- thiazolidinone C5-CH3); 2.64-3.12 (2H, m, CH2-C6H5);
corded on a VG Zab Spec (70 eV) mass spectrometer. 3.98-4.07 (2H, m, N-CH2); 4.39 (1H, q, = 7.1 Hz,
ν
1
δ
J
J
Elemental analyses were performed on a Carlo Erba thiazolidinone C5-H); 7.00 (1H, s, OH); 7.31-7.60 (15H,
1106 elemental analyzer. All chemicals were obtained m, Ar-H), 10.20 (1H, s, NH); EIMS (70 eV) m/z (%):
from Merck.
459 (M+, 12), 442 (8), 277 (5), 249 (70), 234 (83), 105
(100, base peak), 104 (71), 77 (44). Anal. Calcd for
C26H25N3O3S: C, 67.95; H, 5.48; N, 9.14. Found: C,
67.53; H, 5.64; N, 9.10.
General procedure for the synthesis of com-
pounds (3a-j)
To a suspension of 1-(
4-alkyl/arylthiosemicarbazides
ethanol (25 ml) were added anhydrous sodium acetate drazono]-5-methyl-4-thiazolidinone (3d)
(0.2 mol) and ethyl 2-bromopropionate (0.05 mol). The Yield 88%; m.p. 152-153oC; IR (KBr): (cm-1) 3626
reaction mixture was refluxed for 5 h, cooled, diluted (OH), 3311 (NH), 1723, 1674 (C=O); H-NMR (400
α,α
-diphenyl-
α-hydroxy)acetyl-
2
(0.05 mol) in absolute 3-Benzyl-2-[((
α,α-diphenyl-α-hydroxy)acetyl)hy-
ν
1
with water and allowed to stand overnight. The cry- MHz, DMSO-d6):
stals were filtered, dried and purified by crystalliza- thiazolidinone C5-CH3); 4.62 (1H, q,
δ
(ppm) 1.68 (3H, d,
J
= 7.1 Hz,
= 7.1 Hz,
J
tion from ethanol or ethanol/water.
thiazolidinone C5-H); 5.00 (2H, s, N-CH2); 7.00 (1H, s,
OH); 7.41-7.58 (15H, m, Ar-H), 10.20 (1H, s, NH); EIMS
3-Ethyl-2-[(( -diphenyl-α
α
,
α
-hydroxy)acetyl)hydraz- (70 eV) m/z (%): 445 (M+, observed with increased
ono]-5-methyl-4-thiazolidinone (3a)
intensity), 408 (5), 263 (83), 262 (90), 235 (8), 220 (5),
Yield 78%; m.p. 168-169oC; IR (KBr):
ν
(cm-1) 3625 183 (35), 105 (93), 91 (100, base peak), 77 (68). Anal.
1
(OH), 3217 (NH), 1715, 1659 (C=O); H-NMR (200 Calcd for C25H23N3O3S: C, 67.39; H, 5.20; N, 9.43.
MHz, DMSO-d6): (ppm) 1.13 (3H, t, = 7.0 Hz, N- Found: C, 67.26; H, 4.99; N, 9.42.
CH2-CH3); 1.51 (3H, d, = 7.1 Hz, thiazolidinone C5-
CH3); 3.68 (2H, q, = 7.0 Hz, N-CH2); 4.35 (1H, q,
7.1 Hz, thiazolidinone C5-H); 6.88-7.54 (11H, m, Ar-H drazono]-5-methyl-4-thiazolidinone (3e)
and OH); 9.91 (1H, s, NH); EIMS (70 eV) m/z (%): 383 Yield 95%; m.p. 200-201oC; IR (KBr): (cm-1) 3464
(M+, 0.4), 365 (45), 336 (29), 208 (20), 201 (11), 183 (OH), 3279 (NH), 1725, 1656 (C=O); H-NMR (200
(94), 173 (34), 165 (36), 158 (32), 130 (8), 105 (100, MHz, DMSO-d6): (ppm) 1.63 (3H, d, = 7.1 Hz, thi-
base peak), 77 (42). Anal. Calcd for C20H21N3O3S: C, azolidinone C5-CH3); 4.53 (1H, q, = 7.1 Hz, thiazoli-
δ
J
J
J
J
=
3-Phenyl-2-[((α,α-diphenyl-α-hydroxy)acetyl)hy-
ν
1
δ
J
J
62.64; H, 5.52; N, 10.95. Found: C, 62.45; H, 5.76; N, dinone C5-H); 6.92 (1H, s, OH); 7.23-7.52 (15H, m, Ar-
10.53.
H), 9.96 (1H, s, NH); EIMS (70 eV) m/z (%): 431 (M+,
0.4), 413 (44), 249 (38), 221 (87), 208 (16), 205 (63),
3-Butyl-2-[((α,α-diphenyl-α-hydroxy)acetyl)hydraz- 183 (80), 165 (37), 105 (100, base peak), 77 (59). Anal.
ono]-5-methyl-4-thiazolidinone (3b)
Calcd for C24H21N3O3S: C, 66.80; H, 4.90; N, 9.73.
ν
(cm-1) 3628 Found: C, 67.00; H, 5.27; N, 9.62.
Yield 98%; m.p. 131-132oC; IR (KBr):
1
(OH), 3309 (NH), 1713, 1673 (C=O); H-NMR (200
MHz, DMSO-d6): (ppm) 0.86 (3H, t, = 7.2 Hz, N- 3-(4-Bromophenyl)-2-[((
CH2-CH2-CH2-CH3); 1.22-1.26 (2H, m, N-CH2-CH2-CH2 acetyl)hydrazono]-5-methyl-4-thiazolidinone (3f)
CH3); 1.48-1.55 (5H, m, N-CH2-CH2 and thiazolidinone Yield 98%; m.p. 204-205oC; IR (KBr): (cm-1) 3629
C5-CH3 ); 3.63 (2H, t,
= 7.0 Hz, N-CH2); 4.37 (1H, q, (OH), 3315 (NH), 1761, 1700 (C=O); 1H-NMR (200 MHz,
= 7.1 Hz, thiazolidinone C5-H); 6.92 (1H, s, OH), DMSO-d6): (ppm) 1.53 (3H, d, = 7.1 Hz, thiazoli-
δ
J
α,α-diphenyl-α-hydroxy)
-
ν
J
J
δ
J

4-Thiazolidinones
19
dinone C5-CH3); 4.46 (1H, q,
J
= 7.0 Hz, thiazolidinone 3-(4-Nitrophenyl)-2-[((
α
,
α
-diphenyl-
α
-hydroxy)
C5-H); 6.82 (2H, d,
7.30-7.67 (12H, m, Ar-H), 10.87 (1H, s, NH); EIMS (70 Yield 66%; m.p. 206-207oC; IR (KBr):
eV) m/z (%): 509, 511 (M+, (M+2)+, 13, 14), 491, 493 (5, (OH), 3353 (NH), 1756, 1719 (C=O); 1H-NMR (400 MHz,
6), 326, 328 (16, 16), 299, 301 (20, 21), 284, 286 (56, 57), DMSO-d6): (ppm) 1.71 (3H, d, = 6.5 Hz, thiazoli-
223, 225 (5, 5), 196, 198 (18, 17), 183 (86), 105 (100, dinone C5-CH3); 4.68 (1H, q, = 7.1 Hz, thiazolidinone
base peak), 77 (37). Anal. Calcd for C24H20BrN3O3S: C, C5-H); 7.15 (1H, s, OH); 7.22-7.64 (12H, m, Ar-H), 8.41
56.47; H, 3.94; N, 8.23. Found: C, 56.75; H, 4.19; N, (2H, d, = 8.9 Hz, Ar-H); 11.10 (1H, s, NH); EIMS (70
J
= 8.5 Hz, Ar-H); 6.95 (1H, s, OH); acetyl)hydrazono]-5-methyl-4-thiazolidinone (3j)
ν
(cm-1) 3626
δ
J
J
J
7.92.
eV) m/z (%): 183 (10), 165 (6), 152 (4), 105 (70), 82 (9),
77 (100, base peak), 60 (41), 50 (26). Anal. Calcd for
C24H20N4O5S: C, 60.49; H, 4.23; N, 11.75. Found: C,
3-(4-Chlorophenyl)-2-[((α,α-diphenyl-α-hydroxy)
acetyl)hydrazono]-5-methyl-4-thiazolidinone (3g) 60.22; H, 4.28; N, 11.66.
Yield 96%; m.p. 214-215oC; IR (KBr): (cm-1) 3625
(OH), 3421 (NH), 1764, 1724 (C=O); 1H-NMR (200 MHz,
DMSO-d6): (ppm) 1.53 (3H, d, = 6.3 Hz, thiazoli-
dinone C5-CH3); 4.47 (1H, q,
C5-H); 6.88 (2H, d, = 8.5 Hz, Ar-H); 7.01 (1H, s, OH); desired concentration were prepared with RPMI 1640
ν
Antimicrobial activity
δ
J
All compounds to be tested were dissolved in DMSO
J
= 7.1 Hz, thiazolidinone at a stock concentration of 3200 µg/mL. The final
J
7.30-7.54 (12H, m, Ar-H), 10.98 (1H, s, NH); EIMS (70 medium for Candida species and dermatophytes and
eV) m/z (%): 465, 467 (M+, (M+2)+, 0.7, 0.2), 282 (9), with Mueller-Hinton broth of bacteria. The final
240, 242 (20, 7), 208 (7), 182 (69), 105 (100, base peak), DMSO concentration was reduced to 1%.
78 (58), 63 (60). Anal. Calcd for C24H20ClN3O3S: C,
61.86; H, 4.32; N, 9.01. Found: C, 61.56; H, 4.71; N,
8.99.
Antibacterial activity
MICs were determined by the microbroth dilution
method using the National Committee for Clinical
3-(4-Fluorophenyl)-2-[((
acetyl)hydrazono]-5-methyl-4-thiazolidinone (3h) (Clinical and Laboratory Standards Institute, 2005).
Yield 89%; m.p. 197-198oC; IR (KBr): (cm-1) 3563 Mueller-Hinton broth (Oxoid) was used as the test
(OH), 3360 (NH), 1754, 1715 (C=O); 1H-NMR (200 MHz, medium. An inoculum of approximately 5 105 CFU·
= 6.9 Hz, thiazoli- cm-3 was delivered per well. Serial twofold dilutions of
α,α-diphenyl-α-hydroxy) Laboratory Standards (NCCLS) recommendations
ν
×
DMSO-d6):
dinone C5-CH3); 4.59 (1H, q,
C5-H); 7.03, 7.04 (2H, dd,
δ
(ppm) 1.68 (3H, d,
J
J
= 7.0 Hz, thiazolidinone the test compounds (64-0.25 µg/mL) and extra dilu-
J
= 8.6, 8.7 Hz, Ar-H); 7.09 tions (0.12-0.015 µg/mL) for antibiotic standards were
(1H, s, OH); 7.32-7.64 (12H, m, Ar-H), 11.00 (1H, s, prepared. Plates were incubated for 16-20 h at 35oC in
NH); EIMS (70 eV) m/z (%): 449 (M+, 0.4), 266 (5), 239 an ambient air incubator. The lowest concentration
(8), 224 (24), 183 (23), 165 (11), 153 (9), 113 (9), 105 of the test compounds inhibiting visible growth was
(100, base peak), 95 (13), 77 (65), 59 (19). Anal. Calcd taken as the MIC value.
for C24H20FN3O3S: C, 64.12; H, 4.48; N, 9.34. Found:
C, 63.99; H, 4.08; N, 9.28.
Antifungal activity for Candida species
MICs were determined by the microbroth dilution
3-(4-Methylphenyl)-2-[((α,α-diphenyl-α-hydroxy) method using the NCCLS (National Committee for
acetyl)hydrazono]-5-methyl-4-thiazolidinone (3i) Clinical Laboratory) Standards recommendations (Re-
Yield 92%; m.p. 174-175oC; IR (KBr): (cm-1) 3478 ference method for broth dilution antifungal suscepti-
(OH), 3321 (NH), 1727, 1679 (C=O); 1H-NMR (400 MHz, bility testing of yeast, 2002). RPMI broth was prepared
DMSO-d6): (ppm) 1.72 (3H, d, = 7.0 Hz, thiazoli- from RPMI 1640 medium (Sigma) supplemented
dinone C5-CH3); 2.49 (3H, s, Ar-CH3), 4.61 (1H, q, with 0.3 g of glutamine per liter, bufferred with 3-(N-
7.1 Hz, thiazolidinone C5-H); 6.94 (2H, d, = 8.1 Hz, morpholino)-propanesulfonic acid (MOPS), and adjust-
ν
δ
J
J
=
J
Ar-H); 7.09 (1H, s, OH); 7.32-7.66 (12H, m, Ar-H), 11.00 ed to pH 7.0. A working suspension of the inoculum
(1H, s, NH); EIMS (70 eV) m/z (%): 445 (M+, observed was prepared by a 1:100 dilution of the 0.5 McFarland
with increased intensity), 262 (27), 235 (33), 234 (52), standards yeast suspension in 0.85% saline followed
220 (90), 219 (45), 183 (16), 165 (7), 131 (7), 105 (100, by a 1:20 dilution in RPMI broth.
base peak), 91 (22), 77 (93), 58 (49). Anal. Calcd for
C25H23N3O3S: C, 67.39; H, 5.20; N, 9.43. Found: C,
67.07; H, 5.42; N, 9.32.
Two-fold dilutions of test compounds from 64 to 0.25
g/mL were prepared with the working suspension
of the inoculum. Extra dilutions (0.12-0.015 mg/mL)
were added for itraconazole. The plates were incubat-
µ

20
N. U. Güzeldemirci et al.
ed at 35oC for 48 h in ambient air. The MIC is the
lowest concentration of a compound that inhibits
growth of the organism as detected visually.
Antifungal activity for dermatophytes
Microdilution method was used according to a
standard protocol by NCCLS (Clinical and Laboratory
Standards Institute, 2005). RPMI 1640 broth with L-
glutamine without sodium bicarbonate was used and
buffered with 3-(N-morpholino)propanesulfonic acid
(MOPS). The medium was adjusted to pH 7.0 at 25oC.
Preparation of inoculum suspensions of dermato-
phytes were based according to the NCCLS guidelines
(National Committee for Clinical Laboratory Standards.
Reference method for broth dilution antifungal suscepti-
bility testing filamentous fungi, 2002) and previously
described procedure (Fernandez-Torres et al., 2002).
The isolates were subcultured on to potato dextrose
agar plates at 28oC, during 7-14 days. The fungal
colonies were covered with 1 mL of sterile 0.85%
Scheme 1. Synthesis of compounds 3a-j
saline, and suspensions were made by gently probing By heating methyl benzilate and hydrazine-hydrate in
the surface with the tip of Pasteur pipette. The ethanol, -diphenyl- -hydroxyacetic acid hydrazide
was obtained.
Hydrazide and alkyl/aryl isothiocyanates were heat-
-diphenyl- -hydroxy)acetyl-
α,α
α
resulting mixture of conidia and hyphal fragments was
withdrawn and transferred to a sterile tube. Heavy
1
particles were allowed to settle for 15-20 min at room ed in ethanol to yield 1-(
α,α
α
temperature; the upper suspension was mixed with a 4-alkyl/arylthiosemicarbazides 2a-j (Ergenç et al.,
vortex for 15 sec. The turbidity of supernatants was 1992). The thiosemicarbazides were then reacted with
measured spectrophotometrically at a wavelength of ethyl 2-bromopropionate in the presence of anhydrous
530 nm, and transmission was adjusted to 65 to 75%. sodium acetate in absolute ethanol to yield 3-alkyl/
These stock suspensions were diluted 1:50 in RPMI aryl-2-[((
medium to obtain the final inoculum sizes, which methyl-4-thiazolidinones 3a
range from 0.4
104 to 5 104 CFU/mL. Microdilu- tures of the obtained compounds were elucidated by
tion plates were prepared and frozen at -70oC until spectral data.
needed. Rows from 2 to 12 contained the series of drug In the IR spectra, some significant stretching bands
dilutions in 100 L volumes and first row contained due to O-H, N-H and C=O were observed at 3629-3464
100
L of drug-free medium, which served as the cm-1, 3421-3217 cm-1 and 1724-1650 cm-1 , respectively.
growth control. Each well was inoculated on the day of A new strong band at 1764-1713 cm-1 in the spectra of
the test with 100 L of the corresponding inoculum. 3a provided firm support for ring closure (Cesur et
This step brought the drug dilutions and inoculum al., 1994). In the 1H-NMR spectra of compounds 3a
size to the final test concentrations given above. The NH protons appeared as a singlet (1H) at 11.10-9.91
microplates of dermatophytes were incubated at 28oC ppm, the C
-CH3 protons appeared as a quartet (1H)
α
,
α
-diphenyl-
α
-hydroxy)acetyl)hydrazono]-5-
-j. (Table I). The struc-
×
×
µ
µ
µ
-j
-j,
H
during 7 days. The microplates were read visually at 4.68-4.35 ppm and CH-CH3 protons appeared as a
with the aid to an inverted reading mirror after 7 days doublet (3H) at 1.72-1.48 ppm which proved the
for dermatophytes. For all drugs, the MIC was defin- closure of 4-thiazolidinone ring (Farghaly et al., 1990).
ed as the lowest concentration showing 100% inhibi- In the EI-MS spectra of the compounds except 3j, the
tion of growth.
molecular ion peaks which appeared in different in-
tensities, also proved the structures. The fragmenta-
tion route of all compounds were in accordance with
the literature (De Lima et al., 2002).
RESULTS AND DISCUSSION
Chemistry
The target compounds were prepared from methyl
Antimicrobial activity
benzilate (
α
,
α
-diphenyl-
α
-hydroxyacetic acid methyl
All of the compounds were evaluated for in vitro
ester) by a three step synthesis as shown in Scheme 1. antibacterial and antifungal activity against repre-

4-Thiazolidinones
21
Table I. Physicochemical data of compounds (3a-j
)
Analysis (calc./found)
Molecular formula
Compound
R
Mp (oC)
168-169
Yield (%)
78
(MW)
C
H
N
3a
C2H5
C20H21N3O3S
(383.47)
C22H25N3O3S
(411.52)
C26H25N3O3S
(459.57)
C25H23N3O3S
(445.54)
C24H21N3O3S
(431.51)
C24H20BrN3O3S
(510.41)
C24H20ClN3O3S
(465.95)
C24H20FN3O3S
(449.50)
62.64
62.45
64.21
64.12
67.95
67.53
67.39
67.26
66.80
67.00
56.47
56.75
61.86
61.56
64.12
63.99
67.39
67.07
60.49
60.22
5.52
5.76
6.12
6.37
5.48
5.64
5.20
4.99
4.90
5.27
3.94
4.19
4.32
4.71
4.48
4.08
5.20
5.42
4.23
4.28
10.95
10.53
10.21
19.56
19.14
19.10
19.43
19.42
19.73
19.62
18.23
17.92
19.01
18.99
19.34
19.28
19.43
19.32
11.75
11.66
3b
3c
3d
3e
3f
C4H9
CH2CH2C6H5
CH2C6H5
C6H5
131-132
155-156
152-153
200-201
204-205
214-215
197-198
174-175
206-207
98
93
88
95
98
96
89
92
66
C6H4Br(4)
C6H4Cl(4)
C6H4F(4)
C6H4CH3(4)
C6H4NO2(4)
3g
3h
3i
C25H23N3O3S
(445.54)
C24H20N4O5S
(476.51)
3j
sentative bacteria: S. aureus ATCC 29213, P. aerugi-
nosa ATCC 27853 and E. coli ATCC 25922 and fungi:
C. albicans ATCC 10231, C. parapsilosis ATCC 22019,
C. krusei ATCC 6258, T. mentagrophytes var. erinacei
NCPF 375, M. gypseum NCPF 580 and T. tonsurans
NCPF 245 using the microbroth dilution method
(Clinical and Laboratory Standards Institute, 2005;
National Committee for Clinical Laboratory Standards.
Reference method for broth dilution antifungal suscepti-
bility testing of yeasts, 2002). As can be seen in Table
II, 3e (R=C6H5), 3f (R= 4-BrC6H4), 3g (R= 4-ClC6H4),
and 3h (R= 4-FC6H4) showed the highest antibacterial
activity. Particularly R= C2H5 and R=C6H5 substituted
derivatives 3a and 3e showed the highest antifungal
activities against C. parapsilosis ATCC 22019 (3a and
Table II. Antibacterial activity of synthesized compounds
3a-j) (MIC g/mL)
(
µ
Compound/
*microorg.
R
A
B
C
3a
3b
3c
3d
3e
3f
3g
3h
C2H5
C4H9
CH2CH2C6H5
CH2C6H5
C6H5
C6H4Br(4)
C6H4Cl(4)
C6H4F(4)
C6H4CH3(4)
C6H4NO2(4)
>64
>64
>64
>64
>32
>32
>32
>64
>64
>64
0.12
>64
>64
>64
>64
>32
>64
>64
>32
>64
>64
0.5
>64
>64
>64
>64
>32
>32
>32
>32
>64
>64
0.015
3e; MIC=16
3e; MIC=16
MIC=16 µg/mL) (Table III).
µ
g/mL), T. tonsurans NCPF 245 (3a and
µ
g/mL) and M. gypseum NCPF 580 (3e
;
3i
3j
ACKNOWLEDGEMENTS
Levofloxacin
*
A
=
S. aureus ATCC 29213, B
E. coli ATCC 25922.
=P. aeruginosa ATCC 27853,
This work was supported by Istanbul University
C
=

22
N. U. Güzeldemirci et al.
Table III. Antifungal activity of synthesized compounds (3a-j) (MIC µg/mL)
Compound/
*microorg.
R
A
B
C
D
E
F
3a
3b
C2H5
C4H9
32
64
16
64
32
64
32
64
32
32
16
32
3c
3d
3e
CH2CH2C6H5
CH2C6H5
C6H5
64
>64>
32
32
32
16
64
>64>
32
>64
64
32
64
32
16
64
64
16
3f
3g
3h
3i
3j
C6H4Br(4)
C6H4Cl(4)
C6H4F(4)
C6H4CH3(4)
C6H4NO2(4)
32
64
64
32
64
0.12
n.t.
64
32
32
64
>64>
0.06
n.t.
64
32
32
64
>64>
0.12
n.t.
64
64
32
64
>64>
n.t.
0.5
64
64
32
64
>64>
n.t.
0.5
64
32
32
32
>64>
n.t.
0.25
Itraconazole
Amphotericin B
*A
=C. albicans ATCC 10231, B=C. parapsilosis ATCC 22019, C=C. krusei ATCC 6258, D=T. mentagrophytes var. erinacei
NCPF 375, E=M. gypseum NCPF 580, F=T. tonsurans NCPF 245, n.t.=not tested.
Bondock, S., Khalifa, W., and Fadda, A. A., Synthesis and
Research Fund (Project Number: 1179/070998).
antimicrobial evaluation of some new thiazole, thiazolidi-
none and thiazoline derivatives starting from 1-chloro-
3,4-dihydronaphthalene-2-carboxaldehyde. Eur. J. Med.
Chem., 42, 948-954 (2007).
Cesur, N., Cesur, Z., Ergenç, N., Uzun, M., Kiraz, M.,
Kasimoglu Ö., and Kaya D., Synthesis and antifungal
activity of some 2-aryl-3-substituted 4-thiazolidinones.
Synthese und antimykotische Aktivität einiger 2-Aryl-3-
REFERENCES
Ali, M. M. and Hassan, S. A., Role of some newly synthesized
tetrahydronaphthalenthiazol derivatives as anticancer
compounds. Int. J. Cancer Res., 3, 103-110 (2007).
Amin, K. M., Abdel Rahman, D. E., and Al-Eryani, Y. A.,
Synthesis and preliminary evaluation of some substituted
substituierter 4-Thiazolidinone. Arch. Pharm. (Weinheim)
,
coumarins as anticonvulsant agents. Bioorg. Med. Chem.
16, 5377-5388 (2008).
,
327, 271-272 (1994).
Çapan, G., Ulusoy, N., Ergenç, N., Ekinci, A. C., and Vidin,
A., Synthesis and anticonvulsant activity of new 3-[(2-
furyl)carbonyl]amino-4-thiazolidinone and 2-[(2-furyl)
Aquino, T. M., Liesen, A. P., Silva, R. E. A., Lima, V. T.,
Carvalho, C. S., Faria, A. R., Araújo, J. M., Lima, J. G.,
Alves, A. J., Melo, E. J. T., and Góes, A. J. S., Synthesis,
anti-Toxoplasma gondii and antimicrobial activities of
benzaldehyde 4-phenyl-3-thiosemicarbazones and 2-
[(phenylmethylene)hydrazono]-4-oxo-3-phenyl-5-thiazoli-
dineacetic acids. Bioorg. Med. Chem., 16, 446-456 (2008).
Archana, V. K. and Srivastava, A. K., Synthesis of newer
thiadiazolyl and thiazolidinonyl quinazolin-4(3H)-ones as
potential anticonvulsant agents. Eur. J. Med. Chem., 37,
873- 882 (2002).
Balzarini, J., Orzeszko, B., Maurin, J. K., and Orzeszko, A.,
Synthesis and anti-HIV studies of 2-adamantyl-substi-
tuted thiazolidin-4-ones. Eur. J. Med. Chem., 42, 993-
1003 (2007).
Bhati, S. K. and Kumar, A., Synthesis of new substituted
azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino[6,5-b]indoles
as promising anti-inflammatory agents. Eur. J. Med.
Chem., 43, 2323-2330 (2008).
carbonyl]hydrazono-4-thiazoline derivatives. Il Farmaco
,
51, 729-732 (1996).
Çapan, G., Ulusoy, N., Ergenç, N., and Kiraz, M., New 6-
phenylimidazo[2,1-b]thiazole derivatives: Synthesis and
antifungal activity. Monatsh. Chem., 130, 1399-1407
(1999).
De Lima, W. T., De Lima, J. G., and Góes, A. J. S., Spectros.
Lett., 35, 137-144 (2002).
Diurno, M. V., Mazzoni, O., Correale, G., Monterrey, I. G.,
Calignano, A., La Rana, G., and Bolognese, A., Synthesis
and structure-activity relationships of 2-(substituted
phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-
4-ones acting as H1-histamine antagonists. Il Farmaco
,
54, 579-583 (1999).
Ergenç, N., Ilhan, E., and Ötük, G., Synthese und biologische
Wirkung einiger 1,4-disubstituierter Thiosemicarbazide
und deren 1,2,4-Triazol-5-thion-Derivate. Pharmazie, 47,

4-Thiazolidinones
23
59-60 (1992).
Küçükgüzel, G., Kocatepe, A., De Clercq, E., Sahin, F., and
Güllüce, M., Synthesis and biological activity of 4-thiazo-
lidinones, thiosemicarbazides derived from diflunisal
hydrazide. Eur. J. Med. Chem., 41, 353-359 (2006).
Küçükgüzel, S. G., Oruç, E. E., Rollas, S., Sahin, F., and
Özbek, A., Synthesis, characterisation and biological
activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and
some related compounds. Eur. J. Med. Chem., 37, 197-206
(2002).
Farghaly, A. M., Habib, N. S., Khalil, M. A., El-Sayed, O. A.,
and Bistawroos, A. E., Synthesis of novel 2-substituted
quinoline derivatives: Antimicrobial, inotropic, and chro-
notropic activities. Arch. Pharm. (Weinheim), 323, 247-
251 (1990).
Fernandez-Torres, B., Cabanes, F. J., Carillo-Munoz, A.,
Esteban, A., Inza, I., Abarca, L., and Guarro, J., Collabo-
rative evaluation of optimal antifungal susceptibility
testing canditions for dermatophytes. J. Clin. Microbiol.
40, 3999-4003 (2002).
Frère, J.-M., Beta-lactamases and bacterial resistance to
antibiotics. Mol. Microbiol., 16, 385-395 (1995).
Goel, B., Ram, T., Tyagi, R., Bansal, E., Kumar, A., Mukherjee,
D., and Sinha, J. N., 2-Substituted-3-(4-bromo-2-carboxy-
phenyl)-5-methyl-4-thiazolidinones as potential anti-in-
flammatory agents. Eur. J. Med. Chem., 34, 265-269 (1999).
Gürsoy, A. and Terzioglu, N., Synthesis and isolation of new
regioisomeric 4-thiazolidinones and their anticonvulsant
activity. Turk. J. Chem., 29, 247-254 (2005).
,
Mishra, P., Lukose, T., and Kashaw, S. K., Synthesis and
antimicrobial evaluation of some novel 2-imino-3-(4’-car-
boxamido pyridyl)-5-arylidene-4-thiazolidinones and their
brominated derivatives. Indian J. Pharm. Sci., 69, 665-
668 (2007).
National Committee for Clinical Laboratory Standards. Re-
ference method for broth dilution antifungal susceptibility
testing filamentous fungi; Approved standard. M38-A.
National Commitee for Clinical Laboratory Standards
(2002).
Özkirimli, S., Kazan, F., and Tunali, Y., Synthesis,
antibacterial and antifungal activities of 3-(1,2,4-triazol-
3-yl)-4-thiazolidinones. J. Enzymn Inhib. Med. Chem., 23,
1-6 (2008).
Ilhan, E. and Ergenç, N., Synthese und Reaktivität von 3-
substituierten Thiazolidin-2,4-dion-2-(
hydroxyacetyl)hydrazonen 3-Substituted Thiazolidine-
2,4-dione-2-( -diphenyl- -hydroxyacetyl)hydrazones.
α, α-diphenyl-α-
α,α
α
Rao, A., Balzarini, J., Carbone, A., Chimirri, A., De Clercq,
E., Monforte, A. M., Monforte, P., and Pannecouque, C.,
Zappalà M., 2-(2,6-Dihalophenyl)-3-(pyrimidin-2-yl)-1,3-
thiazolidin-4-ones as non-nucleoside HIV-1 reverse tran-
scriptase inhibitors. Antiviral Res., 63, 79-84 (2004).
Rao, A., Balzarini, J., Carbone, A., Chimirri, A., De Clercq,
E., Monforte, A. M., Monforte, P., Pannecouque, C., and
Zappalà, M., Synthesis of new 2,3-diaryl-1,3-thiazolidin-
4-ones as anti- HIV agents. Il Farmaco, 59, 33-39 (2004).
Rao, A., Carbone, A., Chimirri, A., De Clercq, E., Monforte,
A. M., Monforte, P., Pannecouque, C., and Zappalà, M.,
Synthesis and anti-HIV activity of 2,3-diaryl-1,3-thiazoli-
din- 4-ones. Il Farmaco, 58, 115-120 (2003).
Rawal, R. K., Tripathi, R., Katti, S. B., Pannecouque, C., and
De Clercq, E., Design and synthesis of 2-(2,6-dibromo-
phenyl)-3-heteroaryl-1,3-thiazolidin-4-ones as anti-HIV
agents. Eur. J. Med. Chem., 43, 2800-2806 (2008).
Rida, S. M., Ashour, F. A., El-Hawash, S. A. M., ElSemary,
M. M., Badr, M. H., and Shalaby, M. A., Synthesis of some
novel benzoxazole derivatives as anticancer, anti-HIV-1
and antimicrobial agents. Eur. J. Med. Chem., 40, 949-
959 (2005).
Arch. Pharm., 325, 453-454 (1992).
Ilhan, E., Ergenç, N., Ulusoy, N., and Ötük-Sanis, G., Syn-
these und antimikrobie einiger 4-Arylidenamino-3-(
diphenyl- -hydroxymethyl)-1,4-dihydro-5H-1,2,4-triazol-
5-thione und 6-Aryl-3-( -diphenyl- -hydroxymethyl)-
α,α-
α
α,α
α
7H-s-triazolo[3,4-b][1,3,4]thiadiazine. Pharmazie, 51, 123-
124 (1996).
Ilhan, E., Ergenç, N., Uzun, M., and Kaya, D., Synthese von
6-Benzyliden-2-(α,α-diphenyl-α-hydroxyacetyl)-thiazolo
[3,2-b]-s-triazol-5-onen als potentiell biologisch wirksame
Stoffe. Arch. Pharm., 327, 825-826 (1994).
Kaplancikli, Z. A., Turan-Zitouni, G., Özdemir, A., and
Revial, G., Synthesis and anticandidal activity of some
imidazopyridine derivatives. J. Enzyme Inhib. Med.
Chem., 23, 866-870 (2008).
Karali, N., Gürsoy, A., Kandemirli, F., Shvets, N., Kaynak,
F. B., Özbey, S., Kovalishyn, V., and Dimoglo, A., Synthesis
and structure-antituberculosis activity relationship of
1H-indole-2,3-dione derivatives. Bioorg. Med. Chem., 15,
5888-5904 (2007).
Kavitha, C. V., Basappa, S., Swamy, N., Mantelingu, K.,
Doreswamy, S., Sridhar, M. A., Prasad, S., and Rangappa,
K. S., Synthesis of new bioactive venlafaxine analogs:
Novel thiazolidin-4-ones as antimicrobials. Bioorg. Med.
Chem., 14, 2290-2299 (2006).
Kumar, A. and Rajput, C. S., Synthesis and anti-inflamma-
tory activity of newer quinazolin-4-one derivatives. Eur.
J. Med. Chem., 44, 83-90 (2009).
Shah, T. J. and Desai, V. A., Synthesis of some novel fluori-
nated 4-thiazolidinones containing amide linkages and
their antimicrobial screening. Arkivoc, 14, 218-228 (2007).
Siddiqui, I. R., Singh, P. K., Singh, J., and Singh, J., Syn-
thesis and fungicidal activity of novel 4,4’-bis(2”-aryl-5”-
methyl/unsubstituted-4”-oxo-thiazolidin-3”-yl)bibenzyl. J.
Agric. Food Chem., 51, 7062-7065 (2003).
Kumar, P. R., Yadav, M. S., Kumar, M. M. K., and Rao, T. S.,
Synthesis and antimicrobial activity of some new sub-
stituted aryloxy-4-thiazolidinones. E-J. Chem., 3, 44-48
(2006).
Ulusoy, N., Çapan, G., Ergenç, N., Ekinci, A. C., and Vidin,
A., Synthesis, characterization and anticonvulsant activity
of new 4-thiazolidinone and 1,2,4-triazole-3-thione deriva-
tives. Acta Pharm. Turc., 40, 5-8 (1998).

24
N. U. Güzeldemirci et al.
Ulusoy, N., Çapan, G., Ergenç, N., Ötük, Sanis, G., Kiraz,
M., and Kaya, D., Synthesis and antimicrobial activity of
novel imidazo[2,1-b]thiazolyl acetyl amino/hydrazono 4-
thiazolidinones. Synthesis and antimicrobial activity of
novel imidazo[2,1-b]thiazolyl acetyl amino/hydrazono 4-
thiazolidinones. Acta Pharm. Turc., 39, 181-186 (1997).
Ulusoy, N., Ergenç, N., Ekinci, A. C., and Özer, H., Synthe-
sis and anticonvulsant activity of some new arylidenehy-
drazides and 4-thiazolidinones. Monatsh. Chem., 127,
1197-1202 (1996).
1315 (2002).
Vigorita, M. G., Ottanà, R., Monforte, F., Maccari, R., Trovato,
A., Monforte, M. T., Taviano, M. F., Synthesis and anti-
inflammatory, analgesic activity of 3,3’-(1,2- ethanediyl)-
bis[2-aryl-4-thiazolidinone] chiral compounds. Part 10.
Bioorg. Med. Chem. Lett., 11, 2791-2794 (2001).
Wayne, P. A., Clinical and Laboratory Standards Institute.
Performance standards for antimicrobial testing, 15th
informational supplement. M100-S15, (2005).
Wayne, P. A., National Committee for Clinical Laboratory
Standards. Reference method for broth dilution anti-
fungal susceptibility testing of yeasts; Approved standard-
2nd Edition. M27-A2, (2002).
Ulusoy, N., Kiraz, M., and Küçükbasmaci, Ö., New 6-(4-Bro-
mophenyl)-imidazo[2,1-b]thiazole derivatives: Synthesis
and antimicrobial activity. Monatsh. Chem., 133, 1305-