4-Thiazolidinone derivatives as potent antimicrobial agents: Microwave-assisted synthesis, biological evaluation and docking studies

Article abstract of DOI:10.1039/c4md00399c

As a part of our ongoing research in the development of new antimicrobials, herein, we report the synthesis of ten compounds which combine three bioactive moieties: thiazole, adamantane and 4-thiazolidinone. Evaluation of their antibacterial activity revealed that the newly synthesized compounds exhibited remarkable growth inhibition of a wide spectrum of Gram-positive bacteria, Gram-negative bacteria and fungi. The majority of the compounds displayed greater antibacterial activity than the reference drugs (ampicillin and streptomycin), while the antifungal activity was significantly higher than that of the reference drugs bifonazole and ketoconazole. Additionally, the title compounds were screened for HIV-1 reverse transcriptase inhibitory activity, showing no significant activity. Moreover, docking studies were performed in order to explore possible binding modes at the MurB protein of S. aureus. This journal is

Full text of DOI:10.1039/c4md00399c

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4-Thiazolidinone derivatives as potent
antimicrobial agents: microwave-assisted
Cite this: DOI: 10.1039/c4md00399c
synthesis, biological evaluation and docking studies
a
a
a
Eleni Pitta, Evangelia Tsolaki, Athina Geronikaki, Jovana Petrovic,b
*
´
Jasmina Glamoclija,b Marina Sokovic,b Emmanuele Crespan,c Giovanni Maga,c
ˇ
´
Shome S. Bhuniade and Anil K. Saxenade
As a part of our ongoing research in the development of new antimicrobials, herein, we report the synthesis
of ten compounds which combine three bioactive moieties: thiazole, adamantane and 4-thiazolidinone.
Evaluation of their antibacterial activity revealed that the newly synthesized compounds exhibited
remarkable growth inhibition of a wide spectrum of Gram-positive bacteria, Gram-negative bacteria and
fungi. The majority of the compounds displayed greater antibacterial activity than the reference drugs
(ampicillin and streptomycin), while the antifungal activity was significantly higher than that of the
reference drugs bifonazole and ketoconazole. Additionally, the title compounds were screened for HIV-1
reverse transcriptase inhibitory activity, showing no significant activity. Moreover, docking studies were
performed in order to explore possible binding modes at the MurB protein of S. aureus.
Received 11th September 2014
Accepted 31st October 2014
DOI: 10.1039/c4md00399c
www.rsc.org/medchemcomm
pharmacologically compatible moieties such as thiazole, thia-
zolidinone and adamantane within one frame.
1. Introduction
Thiazole is one of the most intensively investigated
classes14–19 of aromatic ve-membered heterocycles and its
derivatives have a variety of medical applications such as
bacteriostatics, antibiotics,20 diuretics,21 local anaesthetics,22,23
anti-inammatories,24 analgesics,25,26 antipyretics,25 anti-
HIV,27,28 etc. Thiazolidin-4-ones are known to possess a wide
range of biological activities, such as antibacterial,29–33 anti-
fungal,29–33 antiviral,34–36 anti-inammatory,32 antituber-
cular,37–39 etc. Furthermore, adamantane is an interesting
moiety in medicinal chemistry known for its antiviral,40–43
antimicrobial,44–46 anti-inammatory16,47 and anti-Alzheimer's48
activities.
Therefore, in this paper we report the synthesis of ten 2-aryl-
3-[4-(adamantan-1-yl)thiazol-2-yl] thiazolidinone-4-ones and
their biological evaluation against a panel of Gram-positive
bacteria, Gram-negative bacteria, fungi and HIV-1 reverse
transcriptase. Furthermore, docking studies of the most active
and one of the least active compounds were performed in order
to explore their potential binding mode at the MurB protein of
S. aureus.
During the past decades, rapid scientic progress has been
made in the treatment of infectious diseases. However, they still
remain a serious and challenging health problem due to several
factors which have led to the re-emergence of these diseases.
Antibiotic resistance, population increase, international travel,
migration, increase in the number of immune-suppressed
patients, and climate change are some of the factors that play a
signicant role in the battle against infectious diseases.1–5
In order to keep microorganisms' resistance under control,
careful use of existing antimicrobial drugs and the design of
novel drugs with different modes of action (e.g. linezolid6–8) are
required.9–12
In continuation of our research on bioactive molecules,13 we
designed and synthesized a series of 2-aryl-3-[4-(adamantan-1-yl)-
thiazol-2-yl] thiazolidinone-4-one derivatives. We emphasized
the strategy of combining three chemically different, but
aDepartment of Medicinal Chemistry, School of Pharmacy, Aristotle University of
Thessaloniki, 54124, Thessaloniki, Greece. E-mail: geronik@pharm.auth.gr; Fax:
+30 23 1099 7612; Tel: +30 23 1099 7616
bMycological Laboratory, Department of Plant Physiology, Institute for Biological
2. Results and discussion
2.1. Chemistry
ˇ
´
Research Sinisa Stankovic, University of Belgrade, Bulevar Despota Stefana 142,
11000, Belgrade, Serbia. E-mail: mris@ibiss.bg.ac.rs; Tel: +381 1 1207 8419
cInstitute of Molecular Genetics, IGM-CNR, via Abbiategrasso 207, 27100, Pavia, Italy.
E-mail: maga@igm.cnr.it; Fax: +39 38 2422 286; Tel: +39 38 2546 354
The nal compounds 3a–j were prepared by the one-pot three
component reaction according to Scheme 1. 4-(Adamantan-1-yl)
thiazol-2-amine (2) was prepared from 1-adamantyl bromo-
dAcademy of Scientic and Innovative Research, 110001, New Delhi, India
eMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow, 226001, India. E-mail: anilsaxenagiper@gmail.com; Tel: +91 52 2400 4280 methyl ketone and thiourea according to the literature.16
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Scheme 1 Synthesis of the title compounds 3a–j. Reaction conditions: (i) isopropanol, r.t., 30 min; (ii) abs EtOH, m.w. irradiation, 110–130 ꢃC,
20–60 min.
Subsequently, the reaction of the 4-(adamantan-1-yl)thiazol-2-
The best antibacterial activity was obtained for compound
amine with differently substituted aromatic aldehydes was 3d, with MICs from 0.9–6.25 mmol mlꢀ1 ꢁ 10ꢀ2 and MBCs from
performed in the presence of mercaptoacetic acid in excess in 1.53–12.5 mmol mlꢀ1 ꢁ 10ꢀ2. The lowest antibacterial activity
absolute ethanol under microwave irradiation to deliver the among all compounds tested herein was obtained for 3e with
nal products (3a–j).28,49 Overall, the reactions proceeded MICs from 21.5–43.0 mmol mlꢀ1 ꢁ 10ꢀ2 and MBCs from 43.0–
smoothly in moderate yields from 20–60%.
86.0 mmol mlꢀ1 ꢁ 10ꢀ2
.
Structures and purity of the nal compounds 3a–j were
The most sensitive bacterial species was S. typhimurium with
conrmed by 1H NMR, 13C NMR, UPLC-MS and elemental MIC values from 0.9–21.9 mmol mlꢀ1 ꢁ 10ꢀ2 and MBC values
analysis. In the 1H NMR spectra, chemical shis of the nal from 1.53–43.8 mmol mlꢀ1 ꢁ 10ꢀ2, followed by M. avus (MIC:
compounds appeared in the region of d 1.45–1.96 (Ad), 3.98– 3.06–21.9 mmol mlꢀ1 ꢁ 10ꢀ2 and MBC: 6.25–43.8 mmol mlꢀ1
ꢁ
4.04 (thiazolidinone, 5-HAHB), 4.15–4.39 (thiazolidinone, 5- 10ꢀ2). L. monocytogenes was the most resistant species with
HAHB), 6.62–6.79 (thiazolidinone, 2-H) and 6.74–8.19 inhibitory activity in the range of 1.53–43.8 mmol mlꢀ1 ꢁ 10ꢀ2
(aromatic). In 13C NMR spectra, chemical shis of the nal and bactericidal at 12.5–86.0 mmol mlꢀ1 ꢁ 10ꢀ2, for almost all
compounds appeared in the region of d 27.8–27.9 (ada- tested samples, apart from compounds 3a and 3f.
mantane), 32.3–33.9 (C-5, thiazolidinone), 35.7–35.8 (ada-
The standard drugs streptomycin and ampicillin, used as
mantane), 36.2–36.3 (adamantane), 55.2–56.3 (CH3O), 59.0–63.0 positive controls, were also active against all bacteria. The range
(C-2, thiazolidinone), 105.4–163.2 (aromatic) and 170.1–170.6 of MICs for streptomycin was 4.3–25.8 mmol mlꢀ1 ꢁ 10ꢀ2 and
(C]O).
MBCs was 8.6–51.6 mmol mlꢀ1 ꢁ 10ꢀ2, while ampicillin showed
slightly lower antibacterial potential with MICs from 24.8–74.4
mmol mlꢀ1 ꢁ 10ꢀ2 and MBCs from 37.2–124.0 mmol mlꢀ1
ꢁ
10ꢀ2. It is worth noting that compounds 3a–j possessed very
strong antibacterial activity, higher than that of ampicillin and
streptomycin. For example, the activity of compound 3d against
S. aureus was ꢂ20-fold higher than that of ampicillin.
Compounds 3e, 3g and 3j were less potent than compounds 3a–
3d, 3f, 3h and 3i, but still they showed higher activity than that
of ampicillin and streptomycin against some bacteria.
2.2. Biological evaluation
2.2.1. Antimicrobial activity. The synthesized compounds
were assayed in vitro for their antimicrobial activity against
Gram-positive and Gram-negative bacteria and fungi obtained
from ATCC (American Type of Culture Collection) or clinical/
human isolates. Minimal inhibitory concentrations (MIC) that
inhibited the growth of the tested microorganisms as well as
minimal bactericidal/fungicidal concentrations (MBC/MFC)
were determined using the microdilution method. The results
of antimicrobial activity of the tested compounds 3a–j and
standard antibiotics/antimycotics against a panel of selected
Gram-positive and Gram-negative bacteria and fungi are pre-
sented in Tables 1 and 2, respectively.
The synthesized compounds showed antibacterial activity
against all the tested bacteria, at different levels. MIC values
were in the range of 0.9–43.8 mmol mlꢀ1 ꢁ 10ꢀ2, while MBCs
were in the range of 1.53–86.0 mmol mlꢀ1 ꢁ 10ꢀ2. The anti-
bacterial potential could be presented as follows: 3d > 3c > 3i >
3h > 3b > 3a > 3f > 3g > 3j > 3e.
The structure–activity relationship (SAR) indicated that
shiing chlorine from position 4 (compound 3c) to positions 3
(compound 3b) or 2 (compound 3a) did not affect signicantly
the activity, leading to slightly less active compounds, however
still comparable. The introduction of a second chlorine atom on
the phenyl ring led to enhanced activity in the case of the 2,3-
diCl-substituted compound (3d) which exhibited the best anti-
microbial prole. However, diCl-substitution at the 2 and 6
positions of the phenyl ring (compound 3e) decreased
dramatically the antimicrobial activity. On the other hand, the
introduction of a methoxy group (compound 3i) or nitro group
(compound 3h) at position 4 of the phenyl ring preserved the
antimicrobial activity. In the case of 4-F substituted phenyl, the
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Table 1 Antibacterial activity of tested compounds (3a–j) and antibiotics (MIC and MBC in mmol mlꢀ1 ꢁ 10ꢀ2
)
Compounds
B. cereus
M. avus
S. aureus
L. monocytogenes E. coli
E. cloacae
P. aeruginosa S. typhimurium
3a
3b
3c
3d
3e
3f
3g
3h
3i
MIC MBC
3.06 12.50
1.625 6.25
1.625 6.25
3.06 6.25
4.50 12.50
6.25 12.5
3.06 6.25
3.06 6.25
6.25 12.5
3.06 6.25
1.625 6.25
0.90 1.53
43.00 64.50 43.00 86.00
30.00 50.00 1.53 12.50
42.00 42.00 42.00 63.00
1.625 12.50
6.25 12.50
6.25 12.50
6.25 12.50
6.25 12.50
3.06 12.50
6.25 12.50
6.25 12.50
3.06 6.25
6.25 12.50
6.25 12.50
1.625 12.50
1.53 6.25
6.25 12.50
3.06 6.25
1.625 6.25
1.53 6.25
21.50 43.00
0.90 1.53
21.00 42.00
3.06 12.50
3.06 6.25
MIC MBC
MIC MBC
MIC MBC
MIC MBC 43.00 64.50 21.50 43.00
MIC MBC 30.00 50.00 3.06 6.125
MIC MBC 10.50 21.00 21.00 42.00
6.25 12.50
6.25 12.50
6.25 12.50
21.50 43.00 43.00 43.00 43.00 64.50
1.53 12.50
21.00 21.00
8.50 12.50
3.06 12.50
3.06 12.50
2.00 42.00 42.00 63.00
3.06 6.25
3.06 12.50
0.90 1.53
MIC MBC
MIC MBC
1.625 3.06
1.63 3.06
6.125 12.50
6.25 12.50
3.06 6.125
3.06 6.25
6.125 12.50
6.25 12.50
3.06 12.50
3.06 6.25
3j
MIC MBC 21.90 43.80 21.90 43.80
4.30 8.60 8.60 17.20
MIC MBC 24.80 37.20 24.80 37.20
43.80 65.70 43.80 65.70
17.20 34.40 25.80 51.60
24.80 37.80 37.20 74.40
21.90 43.80 21.90 43.80 43.80 43.80
17.20 34.40 4.30 8.60 27.20 34.40
37.20 49.20 24.79 37.19 74.40 124.00
21.90 43.80
17.20 34.40
24.80 49.20
Strep. MIC MBC
Amp.
activity increased against most of the species apart from B. against all the tested fungi was shown by the following
cereus and S. aureus that dropped signicantly. The introduc- compounds: 3e, 3g and 3j.
tion of bromine at position 4 (compound 3g) or two methoxy
groups at positions 2 and 5 (compound 3j) led to a decrease in and 3i, A. ochraceus was proved to be the most sensitive, fol-
antimicrobial activity. lowed by T. viride and P. funiculosum, while C. albicans was the
Considering all the tested fungi, for compounds 3a–d, 3f, 3h
All the tested compounds showed very good antifungal most resistant to the tested compounds, except compound 3f.
activity against all tested fungi with MICs in the range of 0.021– In the case of compounds 3e, 3g and 3j, the most sensitive
87.60 mmol mlꢀ1 ꢁ 10ꢀ2 and MFCs in the range of 0.045–109.50 fungus appeared to be T. viride and A. niger the most resistant
mmol mlꢀ1 ꢁ 10ꢀ2 (Table 2). The antifungal potential could be one.
presented as follows: 3d > 3b > 3c > 3f > 3h > 3a > 3i > 3g >3e > 3j.
All tested compounds showed excellent antifungal activity in
The best fungistatic activity against all the tested fungi, comparison with commercial antimycotics. MICs for bifonazole
except C. albicans, was found for compound 3d, which showed were in the range of 32.0–64.0 mmol mlꢀ1 ꢁ 10ꢀ2 and MFCs
excellent activity with MIC values of only 0.021–0.042 mmol mlꢀ1 were in the range of 64.0–80.0 mmol mlꢀ1 ꢁ 10ꢀ2, while keto-
ꢁ 10ꢀ2 and MFC values of 0.06 mmol mlꢀ1 ꢁ 10ꢀ2. Compound conazole showed much lower activity with MICs from 38.0–
3f exhibited the best activity against C. albicans with MIC 0.08 475.0 mmol mlꢀ1 ꢁ 10ꢀ2 and MFCs from 95.0–570.0 mmol mlꢀ1
mmol mlꢀ1 ꢁ 10ꢀ2 and MFC 0.14 mmol mlꢀ1 ꢁ 10ꢀ2. The lowest ꢁ 10ꢀ2
.
fungistatic, as well as fungicidal, activity was achieved for
The relationship between structure and antifungal activity
compound 3j (MIC 10.95–87.60 mmol mlꢀ1 ꢁ 10ꢀ2 and MBC revealed that 2,3-diCl, 3-Cl and 4-Cl substitution of the phenyl
21.9–109.50 mmol mlꢀ1 ꢁ 10ꢀ2).
ring (compounds 3d, 3b and 3c, respectively) is favourable and
Compounds 3a–c, 3h and 3i also showed excellent antifungal in agreement with what observed for antibacterial potential. It
activity with MICs and MFCs values slightly lower than was also found that the presence of 3-F, 4-NO2, 2-Cl and 4-OCH3
compound 3d. Lower, but still good, fungistatic and fungicidal groups led to slightly less active compounds but still compa-
activity, higher than that of ketoconazole and bifonazole, rable with the most active ones. On the other hand, 4-Br, 2,6-
Table 2 Antifungal activity of tested compounds (3a–j) and fungicides (MIC and MFC in mmol mlꢀ1 ꢁ 10ꢀ2
)
Compounds
A. fumigatus A. versicolor A. ochraceus A. niger
T. viride
P. funiculosum P. ochrochloron C. albicans
3a
3b
3c
3d
3e
3f
3g
3h
3i
MIC MFC
0.58 1.16
0.29 0.58
0.045 0.07
0.042 0.06
0.58 1.16
0.03 0.07
0.05 0.07
0.021 0.06
21.48 32.22
0.04 0.14
10.51 10.51
0.56 1.13
0.03 0.07
0.045 0.07
0.05 0.07
0.042 0.06
10.74 53.71
0.04 0.14
10.51 42.04
0.14 0.28
0.14 0.29
0.9 1.16
0.03 0.07
0.58 1.16
0.03 0.045
0.03 0.05
0.021 0.06
21.48 21.48
0.12 0.14
10.51 10.51
0.14 0.28
0.58 1.16
0.29 0.58
0.045 0.07
0.042 0.06
21.48 53.71
0.08 0.14
21.02 52.58
0.07 0.14
0.29 0.58
0.58 1.16
0.29 0.58
0.03 0.07
0.021 0.06
21.48 32.22
0.04 0.14
21.02 21.02
0.14 0.28
1.16 2.32
0.58 1.16
0.58 1.16
0.53 1.075
42.96 64.45
0.08 0.14
52.58 73.60
1.13 2.26
MIC MFC
MIC MFC
MIC MFC
MIC MFC 21.48 53.71
MIC MFC 0.08 0.14
MIC MFC 21.02 21.02
0.045 0.07
0.021 0.06
21.48 32.22
0.08 0.14
21.02 31.54
0.35 0.56
MIC MFC
MIC MFC
1.13 4.52
1.17 2.34
0.29 0.58
0.29 0.58
0.14 0.29
0.09 0.14
1.17 2.34
3j
MIC MFC 21.90 32.85
21.90 32.85
38.00 95.00
32.00 64.00
10.95 32.85
38.00 95.00
48.00 80.00
21.90 87.60
38.00 95.00 475.00 570.00 38.00 95.00
48.00 64.00 64.00 80.00 64.00 80.00
21.90 21.90
21.90 43.80
21.90 43.80
380.00 380.00
48.00 64.00
87.60 109.50
38.00 95.00
32.00 48.00
Ket. MIC MFC 38.00 95.00
Bif. MIC MFC 48.00 64.00
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diCl and 2,5-di-OCH3 had negative effects on their antifungal
activity.
According to the presented results it could be noticed that
the antifungal potential of compounds 3a–d, 3f, 3h and 3i is
higher than their antibacterial effect, while compounds 3e, 3g
and 3j exhibited decreased antibacterial as well as antifungal
activity.
2.2.2. HIV-RT inhibitory activity evaluation. Based on our
previous results that compounds 3e and 3g had shown some
inhibitory activity against HIV-1 reverse transcriptase,27
compounds 3a–d, 3f and 3h–j were evaluated for HIV-1 reverse
transcriptase inhibitory activity. The obtained data are pre-
sented in Table 3.
All compounds were assayed at the nal concentration of 4
mM. Only compounds 3e and 3g showed moderate inhibitory
activity and ID50 values (mM) were determined and reported in
our previous publication.27 However, none of the other
compounds showed signicant inhibitory activity at this
concentration.
Fig. 1 (A) The docked conformation of the most active compound
(3d) and (B) one of the least active compounds (3e) at the active site of
the MurB protein of S. aureus. (C) The Cl–p interaction of the 3-Cl
substituent in compound 3d.
2.3. Docking studies on MurB protein of S.aureus
In order to explore the possible binding mode at the MurB
protein of S. aureus (PDB ID: 1HSK), we performed docking
studies for the most active (3d) (MIC ¼ 0.9 mmol mlꢀ1 ꢁ 10ꢀ2
)
)
face to face p–p interaction with PHE274. The Cl–p interaction
was the determining factor governing the activity of the
compounds in the halogen series, as observed in the least active
compound 3e that has the 2,6-dichloro moiety far away from
Phe274 and thus was unable to show the Cl–p interaction. The
thiazolidine-4-one is a potential surrogate of the di-phosphate
moiety, present in UDP-N-acetylenol-pyruvylglucosamine.51 The
keto-group of the thiazolidine moiety formed a hydrogen bond
with GLY249 and the electronegative sulphur atom forms a
hydrogen bond with the side chain of ARG242 that has been
postulated as an important amino acid involved in UDP-N-ace-
tylenol-pyruvylglucosamine binding.52 The thiazole moiety,
attached to the thiazolidine-4-one, formed p–p interactions
with another important residue HIS271.52 The adamantane
moiety resided at the shallow pocket formed by the GLY249,
GLN 253, and ALA272. Thus, the Cl–p interaction appeared to
be the main determinant for enhanced activity.
and one of the least active (3e) (MIC ¼ 43 mmol mlꢀ1 ꢁ 10ꢀ2
compounds using the GLIDE module implemented in the
¨
Schrodinger soware package (Fig. 1). The important interac-
tions of the most active compound 3d (R-isomer) included
hydrogen bond contacts with the backbone nitrogen of GLY249
and side chain nitrogen of ARG242. Apart from the hydrogen
bond contacts, compound 3d was involved in the “edge on” Cl–
p interaction with Phe274 at the active site. The 3-Cl substituent
attached to the phenyl ring of compound 3d had a distance (r ¼
0
˚
˚
3.65 A) from the centroid of PHE274 and a distance (r ¼ 3.13 A)
from one of the ring carbon atoms as shown in Fig. 1C. The
0
˚
˚
difference between |r ꢀ r | was 0.52 A (value above 0.3 A), which
indicated an “edge on” Cl–p interaction with Phe274.50 The
phenyl ring in the 2,3-dichlorophenyl moiety was in hydro-
phobic contact with VAL239 and GLY273, with an additional
Table 3 HIV-RT inhibitory activity of tested compounds (3a–j)
3. Experimental
Residual RT
activity (%)
All commercial reagents and solvents were used without further
purication. Reactions were monitored by TLC on silica gel with
detection by UV light (254 nm) and iodine. TLC analysis was
performed using Polygram® precoated silica gel TLC sheets SIL
G/UV254. Melting points of the compounds were determined
using a MELTEMP II capillary apparatus (LAB Devices, Hollis-
ton, MA, USA) and are uncorrected. All microwave-assisted
reactions were carried out in a dedicated CEM-Discover mono-
mode microwave apparatus, operating at a frequency of 2.45
GHz with continuous irradiation power from 0 to 300 W with
utilization of the standard absorbance level of 300 W maximum
power. Elemental analyses were performed on a Perkin-Elmer
2400 CHN elemental analyzer (The Perkin-Elmer Corporation
Compounds
[I] (mM)
3a
3b
3c
3d
3e
3f
3g
3h
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
99.12
99.35
99.05
100.20
52.52
100.03
59.85
99.27
100.17
80.65
100.00
3.10
3i
3j
DMSO (4%)
Efavirenz
0.10
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Ltd., Lane Beaconseld, Bucks, UK) and all synthesized 1.96 (s, 3H, Ad), 1.74–1.60 (m, 12H, Ad). 13C NMR (101 MHz,
compounds were within 0.4% of the theoretical values. 1H NMR DMSO-d6) d 170.1, 160.2, 154.8, 144.0, 132.6, 130.3, 127.9, 127.7,
and 13C NMR spectra were recorded on a Bruker Avance III 125.0, 105.6, 62.5, 41.3, 36.3, 35.8, 32.4, 27.9. MS (ESI), m/z:
nanobay ultra shield 400 spectrometer or a Bruker AC 300 431.1, 433.1 (3 : 1) [M + H]+. Anal. calcd for C22H23ClN2OS2 (MW
spectrometer. The chemical shi (d) values are expressed in 431): C, 61.31; H, 5.38; N, 6.50%. Found: C, 61.48; H, 5.30; N,
parts per million (ppm) and coupling constants are in Hertz 6.47%.
(Hz). DMSO-d6 was used as the standard NMR solvent. Legend:
3.2.2. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(3-chlorophenyl)
s ¼ singlet, d ¼ doublet, dd ¼ doublet of doublets, t ¼ triplet, thiazolidin-4-one (3b). Yield: 20%, mp: 90–93 ꢃC, Rf ¼ 0.84
1
and m ¼ multiplet.
(petroleum ether/ethylacetate: 8/2). H NMR (400 MHz, DMSO-
ESI-MS spectra were obtained with an Esquire 3000 plus ion d6) d 7.61 (s, 1H, Ph), 7.44 (s, 1H, Ph), 7.39–7.26 (m, 2H, Ph), 6.76
trap mass spectrometer from Bruker Daltonics, using the direct (s, 1H, thiazole, 5-H), 6.63 (s, 1H, thiazolidinone, 2-H), 4.39 (d,
infusion mode. UPLC (Ultra Performance Liquid Chromatog- J ¼ 16.3 Hz, 1H, thiazolidinone, 5-HAHB), 4.02 (d, J ¼ 16.5 Hz,
raphy) was performed using a Waters acquity H-class UPLC 1H, thiazolidinone, 5-HAHB), 1.96 (s, 3H, Ad), 1.76–1.59 (m, 12H,
system coupled to a waters TQD ESI mass spectrometer and a Ad). 13C NMR (101 MHz, DMSO-d6) d 170.1, 160.2, 154.8, 144.0,
waters TUV detector. A waters acquity UPLC BEH C18 1.7 mm 132.6, 130.3, 127.9, 127.7, 125.0, 105.6, 62.5, 41.3, 36.2, 35.8,
2.1–50 mm column was used. Solvent A: water with 0.1% formic 32.4, 27.9. MS (ESI), m/z: 431.2, 433.1 (3.1) [M + H]+. Anal. calcd
acid, solvent B: acetonitrile with 0.1% formic acid. Method: 0.15 for C22H23ClN2OS2 (MW 431): C, 61.31; H, 5.38; N, 6.50%.
min 95% A, 5% B, then in 1.85 min from 95% A, 5% B to 95% B, Found: C, 61.48; H, 5.25; N, 6.46%.
5% A, then 0.25 min (0.350 ml minꢀ1), 95% B, 5% A. The
3.2.3. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(4-chlorophenyl)
wavelength for UV detection was 254 nm. The quasi-molecular thiazolidin-4-one (3c). Yield: 36%, mp: 183–185 ꢃC, Rf ¼ 0.86
ions [M + H]+ were detected.
(petroleum ether/ethylacetate: 8/2). H NMR (400 MHz, DMSO-
d6) d 7.49–7.47 (m, 1H, Ph), 7.47–7.45 (m, 1H, Ph), 7.40–7.37 (m,
1H, Ph), 7.37–7.35 (m, 1H, Ph), 6.77 (s, 1H, thiazole, 5-H), 6.66
(d, J ¼ 0.9 Hz, 1H, thiazolidinone, 2-H), 4.31 (dd, J ¼ 16.5, 1.3
Hz, 1H, thiazolidinone, 5-HAHB), 4.01 (d, J ¼ 16.5 Hz, 1H,
thiazolidinone, 5-HAHB), 1.95 (s, 3H, Ad), 1.74–1.58 (m, 12H,
Ad). 13C NMR (101 MHz, DMSO-d6) d 170.2, 160.3, 154.9, 140.6,
132.4, 128.5, 128.2, 105.7, 62.5, 41.2, 36.3, 35.7, 32.3, 27.8. MS
1
3.1. Procedure for the synthesis of 4-[(3r,5r,7r-) adamantan-
1-yl] thiazol-2-amine (2)
A suspension of thiourea (0.59 g, 7.75 mmol, 2 eq.) in iso-
propanol (39 ml) was added to a solution of 1-adamantyl bro-
momethyl ketone (1 g, 3.89 mmol, 1 eq.) in isopropanol (19.3
ml). The mixture was stirred at room temperature for 30
minutes. Subsequently, the reaction mixture was poured into an
aqueous solution of sodium carbonate (5% w/v) and the formed
precipitate was ltered and recrystallized from ethyl acetate to
deliver the target compound (0.86 g, yield: 94%).
(ESI), m/z: 431.1, 433.0 (3 : 1) [M + H]+. Anal. calcd for C22H23
-
ClN2OS2 (MW 431): C, 61.31; H, 5.38; N, 6.50%. Found: C, 61.50;
H, 5.20; N, 6.57%.
3.2.4. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(2,3-dichlor-
ophenyl)thiazolidin-4-one (3d). Yield: 60%, mp: 154–156 ꢃC,
Rf ¼ 0.80 (petroleum ether/ethylacetate: 8/2). 1H NMR (400
MHz, DMSO-d6) d 7.56 (dd, J ¼ 7.4, 2.0 Hz, 1H, Ph), 7.36–7.24
3.2. General procedure for the synthesis of nal c (3a–j)
A mixture of 4-(adamantan-1-yl)thiazol-2-amine (1.0 mmol), the (m, 2H, Ph), 6.93 (d, J ¼ 1.2 Hz, 1H, thiazole, 5-H), 6.75 (s, 1H,
appropriate substituted benzaldehyde (1.5 mmol) and mercap- thiazolidinone, 2-H), 4.26 (dd, J ¼ 16.2, 1.4 Hz, 1H, thiazolidi-
toacetic acid (5 mmol) was placed in a 10 ml reaction vial con- none, 5-HAHB), 4.08 (d, J ¼ 16.2 Hz, 1H, thiazolidinone, 5-HAHB),
taining absolute ethanol (ꢂ3 ml) and a stirring bar. The vial was 1.91 (s, 3H, Ad), 1.78–1.46 (m, 12H, Ad). 13C NMR (101 MHz,
sealed tightly with a Teon septum, placed into the microwave DMSO-d6) d 170.1, 160.1, 154.8, 141.1, 131.9, 129.7, 128.6, 127.4,
cavity and irradiated at 110–130 ꢃC using 100–150 W as the 125.6, 105.6, 60.4, 41.0, 36.2, 35.7, 32.4, 27.8. MS (ESI), m/z:
maximum power for 20–60 min. Then, the reaction mixture was 465.1, 467.1, 469.1 (9 : 6 : 1) [M + H]+. Anal. calcd for C22H22
-
rapidly cooled by gas jet cooling to ambient temperature. The Cl2N2OS2 (MW 465): C, 56.77; H, 4.76; N, 6.02%. Found: C,
corresponding nal compound precipitated aer cooling and 56.71; H, 4.79; N, 6.06%.
was collected by ltration. The precipitate was taken up with
3.2.5. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(3-uorophenyl)
ethyl acetate and the organic layer was washed with aqueous thiazolidin-4-one (3f). Yield: 39%, mp: 96–99 ꢃC, Rf ¼ 0.81
1
citric acid (5% w/v), water and aqueous sodium hydrogen (petroleum ether/ethylacetate: 8/2). H NMR (400 MHz, DMSO-
carbonate (5% w/v). The organic layer was dried over sodium d6) d 7.41–7.24 (m, 3H, Ph), 7.14–7.04 (m, 1H, Ph), 6.77 (s, 1H,
sulfate and evaporated under reduced pressure to give the pure thiazole, 5-H), 6.66 (s, 1H, thiazolidinone, 2-H), 4.36 (dd,
product.
J ¼ 16.4, 1.2 Hz, 1H, thiazolidinone, 5-HAHB), 4.01 (d, J ¼ 16.4
3.2.1. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(2-chlorophenyl) Hz, 1H, thiazolidinone, 5-HAHB), 1.94 (s, 3H, Ad), 1.73–1.58 (m,
thiazolidin-4-one (3a). Yield: 44%, mp: 112–115 ꢃC, Rf ¼ 0.80 12H, Ad). 13C NMR (101 MHz, DMSO-d6) d 170.2, 161.9 (d, 1JC–F
(petroleum ether/ethylacetate: 8/2). H NMR (400 MHz, DMSO- ¼ 243.8 Hz), 160.2, 154.9, 144.5 (d, 3JC–F ¼ 7.2 Hz), 130.3 (d, 3JC–F
1
4
2
d6) d 7.64–7.58 (m, 1H, Ph), 7.47–7.38 (m, 1H, Ph), 7.38–7.28 (m, ¼ 8.3 Hz), 122.4 (d, JC–F ¼ 2.7 Hz), 114.8 (d, JC–F ¼ 21.1 Hz),
2
3
2H, Ph), 6.77 (s, 1H, thiazole, 5-H), 6.63 (d, J ¼ 1.0 Hz, 1H, 113.8 (d, JC–F ¼ 22.5 Hz), 105.6, 62.5 (d, JC–F ¼ 1.8 Hz), 41.2,
thiazolidinone, 2-H), 4.39 (dd, J ¼ 16.4, 1.3 Hz, 1H, thiazolidi- 36.2, 35.7, 32.2, 27.8. MS (ESI), m/z: 415.2 [M + H]+. Anal. calcd
none, 5-HAHB), 4.02 (d, J ¼ 16.4 Hz, 1H, thiazolidinone, 5-HAHB),
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for C22H23FN2OS2 (MW 414): C, 63.74; H, 5.59; N, 6.76%. Found: medium to verify the absence of contamination and check the
C, 63.70; H, 5.61; N, 6.73%. validity of the inoculum. The tested compounds were dissolved
3.2.6. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(4-nitrophenyl) in 5% DMSO in sterile water and added in broth Triptic Soy
thiazolidin-4-one (3h). Yield: 44%, mp: 190–193 ꢃC, Rf ¼ 0.72 broth (TSB) medium (100 ml) with bacterial inoculum (1.0 ꢁ 104
1
(petroleum ether/ethylacetate: 8/2). H NMR (400 MHz, DMSO- CFU per well) to achieve the desired concentrations (0.001–1.0
d6) d 8.19 (d, J ¼ 8.7 Hz, 2H, Ph), 7.72 (d, J ¼ 8.7 Hz, 2H, Ph), 6.79 mg mlꢀ1) in dilution order. The microplates were incubated for
(d, J ¼ 5.4 Hz, 2H, thiazole, 5-H and thiazolidinone, 2-H), 4.32 24 h at 37 ꢃC. The MICs of the samples were detected following
(d, J ¼ 16.5 Hz, 1H, thiazolidinone, 5-HAHB), 4.05 (d, J ¼ 16.4 Hz, the addition of 40 ml of iodonitrotetrazolium chloride (INT)
1H, thiazolidinone, 5-HAHB), 1.91 (s, 3H, Ad), 1.71–1.46 (m, 12H, (0.2 mg mlꢀ1) and incubation at 37 C for 30 min. The lowest
ꢃ
Ad). 13C NMR (101 MHz, DMSO-d6) d 170.2, 160.2, 154.9, 149.2, concentration that produced a signicant inhibition of the
146.9, 127.7, 123.6, 105.8, 62.1, 41.2, 36.2, 35.7, 32.3, 27.8. MS growth of the bacteria in comparison with the positive control
(ESI), m/z: 442.2 [M + H]+. Anal. calcd for C22H23N3O3S2 (MW was identied as the MIC.
441): C, 59.84; H, 5.25; N, 10.87%. Found: C, 59.80; H, 5.26; N,
10.84%.
MBCs were determined by serial sub-cultivation of 10 ml into
microplates containing 100 ml of TSB. The lowest concentration
3.2.7. 3-(4-(Adamantan-1-yl)thiazol-2-yl)-2-(4-methoxy- that shows no growth aer this sub-culturing was read as the
phenyl)thiazolidin-4-one (3i). Yield: 24%, mp: 114–116 ꢃC, Rf ¼ MBC. Standard drugs, namely streptomycin and ampicillin,
0.67 (petroleum ether/ethylacetate: 8/2). 1H NMR (400 MHz, were used as positive controls. 5% of DMSO in sterile water was
DMSO-d6) d 7.39 (d, J ¼ 8.6 Hz, 2H, Ph), 6.86 (d, J ¼ 8.6 Hz, 2H, used as the negative control. All experiments were performed in
Ph), 6.76 (s, 1H, thiazole, 5-H), 6.62 (s, 1H, thiazolidinone, 2-H), duplicate and repeated three times.
4.31 (d, J ¼ 16.5 Hz, 1H, thiazolidinone, 5-HAHB), 3.99 (d, J ¼
3.3.2. Antifungal activity. The used fungi: Aspergillus fumi-
16.5 Hz, 1H, thiazolidinone, 5-HAHB), 3.71 (s, 3H, CH3O), 1.96 gatus (ATCC 1022), Aspergillus versicolor (ATCC 11730), Asper-
(s, 3H, Ad), 1.76–1.60 (m, 12H, Ad). 13C NMR (101 MHz, DMSO- gillus ochraceus (ATCC 12066), Aspergillus niger (ATCC 6275),
d6) d 170.2, 160.3, 159.0, 154.9, 133.3, 128.2, 113.6, 105.6, 62.9, Trichoderma viride (IAM 5061), Penicillium funiculosum (ATCC
55.2, 41.3, 36.3, 35.8, 32.4, 27.9. MS (ESI), m/z: 427.2 [M + H]+. 36839), Penicillium ochrochloron (ATCC 9112) and Candida
Anal. calcd for C23H26N2O2S2 (MW 426): C, 64.76; H, 6.14; N, albicans (ATCC 10231) were obtained from Mycological Labo-
6.57%. Found: C, 64.71; H, 6.20; N, 6.60%.
ratory, Department of Plant Physiology, Institute for Biological
ˇ
´
3.2.8. 3-[4-(2-Adamantyl)-1,3-thiazol-2-yl]-2-(2,5-dime- Research “Sinisa Stankovic”, University of Belgrade, Serbia.
thoxyphenyl)-1,3-thiazolidin-4-one (3j). Yield: 31%, mp: 161–
The micromycetes were maintained on malt agar and the
1
162 C, Rf ¼ 0.62 (petroleum ether/ethylacetate: 8/2). H NMR cultures were stored at 4 C and sub-cultured once a month.55
(400 MHz, DMSO-d6) d 6.94 (d, J ¼ 9.0 Hz, 1H, Ph), 6.83–6.77 (m, The antifungal assay was carried out by a modied micro-
2H, Ph), 6.74 (s, 1H, thiazole, 5-H), 6.72 (d, J ¼ 1.2 Hz, 1H, dilution technique.56 The fungal spores were washed from the
thiazolidinone, 2-H), 4.15 (dd, J ¼ 16.2, 1.4 Hz, 1H, thiazolidi- surface of agar plates with sterile 0.85% saline containing 0.1%
none, 5-HAHB), 3.98 (d, J ¼ 16.2 Hz, 1H, thiazolidinone, 5-HAHB), Tween 80 (v/v). The spore suspension was adjusted with sterile
3.77 (s, 3H, CH3O), 3.66 (s, 3H, CH3O), 1.94 (s, 3H, Ad), 1.73– saline to a concentration of approximately 1.0 ꢁ 105 in a nal
ꢃ
ꢃ
1.57 (m, 12H, Ad). 13C NMR (101 MHz, DMSO-d6) d 170.6, 160.2, volume of 100 ml per well. The inocula were stored at 4 C for
ꢃ
154.9, 152.7, 150.6, 129.5, 113.9, 113.7, 112.6, 105.4, 59.7, 56.3, further use. Dilutions of the inoculum were cultured on solid
55.3, 41.2, 36.3, 35.7, 33.0, 27.8. MS (ESI), m/z: 457.2 [M + H]+. malt agar to verify the absence of contamination and to check
Anal. calcd for C22H22Cl2N2OS2 (MW 456): C, 63.13; H, 6.18; N, the validity of the inoculum.
6.13%. Found: C, 63.18; H, 6.15; N, 6.16%.
MIC determination was performed by a serial dilution
technique using 96-well microtiter plates. The examined
compounds were diluted in 5% of DMSO in sterile water (0.001–
1.0 mg mlꢀ1) and added in broth Malt medium (MA) with
3.3. Biological evaluation
3.3.1. Antibacterial activity. The following Gram positive inoculum. The microplates were incubated at a rotary shaker
bacteria: Bacillus cereus (clinical isolate), Micrococcus avus (160 rpm) for 72 h at 28 ꢃC. The lowest concentrations without
(ATCC 10240), Staphylococcus aureus (ATCC 6538) and Listeria visible growth (at the binocular microscope) were dened as
monocytogenes (NCTC 7973) and Gram negative bacteria: MICs.
Escherichia coli (ATCC 35210), Enterobacter cloacae (human
The fungicidal concentrations (MFCs) were determined by
isolate), Pseudomonas aeruginosa (ATCC 27853) and Salmonella serial subcultivation of 2 ml of tested fractions dissolved in
typhimurium (ATCC 13311) were used. The microorganisms medium and inoculated for 72 h, into microtiter plates con-
were obtained from the Mycological laboratory, Department of taining 100 ml of broth per well and further incubation for 72 h
ꢃ
Plant Physiology, Institute for biological research “Sinisa at 28 C. The lowest concentration with no visible growth was
´
Stankovic”, University of Belgrade, Serbia.
dened as the MFC indicating 99.5% killing of the original
The minimum inhibitory (MIC) and minimum bactericidal inoculum. The fungicides bifonazole and ketoconazole were
(MBC) concentrations were determined by the microdilution used as positive controls (1–3500 mg mlꢀ1). Three independent
method.53,54 Briey, fresh overnight culture of bacteria was experiments were performed in duplicate.
adjusted by using the spectrophotometer to a concentration of
3.3.3. In vitro HIV-RT kit assay. The RNA-dependent DNA
1 ꢁ 105 CFU mlꢀ1. Dilutions of inocula were cultured on solid polymerase activity of HIV-1 reverse transcriptase (RT) was
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assayed in a reaction buffer containing 50 mM Tris–HCl (pH Furthermore, docking studies for compounds 3d and 3e were
8.0), 1 mM dithiothreitol (DTT), 0.2 mg mlꢀ1 bovine serum performed in order to explore their possible binding mode at
albumin (BSA) and 2% glycerol. Thus, 2–4 nM RT was incubated the MurB protein of S. aureus.
at 37 ꢃC with 10 mM MgCl2, 0.5 mg of poly(rA):oligo(dT)10:1
The promising properties of this new class of antibacterial
(0.3 mM 30-OH ends), 10 mM radioactive 2'deoxy-thymidine substances deserve further investigation in order to clarify the
50-triphosphate (3[H]dTTP) (1 Ci mmolꢀ1), for 15 min. Then, 20 mode of action at the molecular level, responsible for the
ml aliquots were spiked on glass ber lters GF/C (Whatman Int. activity observed.
Ltd, Maidstone, England) and, immediately, immersed in 5%
ice-cold trichloroacetic acid (TCA) (AppliChem GmbH, Darm-
stadt). Filters were washed three times with 5% TCA and once
with ethanol for 5 minutes, then dried and, nally, added with
Notes and references
EcoLume® Scintillation cocktail (ICN, Research Products Divi-
sion, Costa Mesa, CA USA) to detect the acid-precipitable
radioactivity by scintillation counting. Incorporation of radio-
active dTTP into poly(rA):oligo (dT) was tested in the absence or
presence of the tested compounds (4 mM).
1 F. C. Tenover and L. C. McDonald, Curr. Opin. Infect. Dis.,
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implemented in the Schrodinger 9 suite.58 The 3D structures of
¨
the ligands were sketched in the maestro workspace using the
drawing tools in maestro window. The 3D structures were
geometry optimized by clean up geometry and subsequent
ligand preparation was performed utilizing the Ligprep
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3.4.2. Molecular docking and scoring. The molecular
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module implemented in the Schrodinger 9 suite.58 The receptor
¨
grid was generated using the centroid of the residues ARG188,
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acetylglucosamine (EP-UDPGlcNAc) with S. aureus MurB.52 The
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All tested compounds 3a–j exhibited a remarkable growth
inhibition against a wide spectrum of Gram-positive bacteria,
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´
antifungal prole with MICs from 0.021 to 0.53 mmol mlꢀ1
ꢁ
10ꢀ2 and MFCs from 0.06 to 1.075 mmol mlꢀ1 ꢁ 10ꢀ2
.
The most sensitive bacterial species to the tested compounds
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was the most resistant.
Moreover, the title compounds were screened for HIV-1 RT
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