Synthesis, molecular structure investigations and antimicrobial activity of 2-thioxothiazolidin-4-one derivatives

Article abstract of DOI:10.1016/j.molstruc.2014.10.038

A variety of 2-thioxothiazolidin-4-one derivatives were prepared and their in vitro antimicrobial activities were studied. Most of these compounds showed significant antibacterial activity specifically against Gram-positive bacteria, among which compounds

Full text of DOI:10.1016/j.molstruc.2014.10.038

Accepted Manuscript
Synthesis, Molecular Structure Investigations and Antimicrobial Activity of 2-
Thioxothiazolidin-4-one Derivatives
Assem Barakat, Hany J. Al-Najjar, Abdullah Mohammed Al-Majid, Saied M.
Soliman, Yahia Nasser Mabkhot, Mohamed H.M. Al-Agamy, Hazem A.
Ghabbour, Hoong-Kun Fun
PII:
S0022-2860(14)01051-5
DOI:
http://dx.doi.org/10.1016/j.molstruc.2014.10.038
MOLSTR 21034
Reference:
Journal of Molecular Structure
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 August 2014
24 September 2014
16 October 2014
Please cite this article as: A. Barakat, H.J. Al-Najjar, A.M. Al-Majid, S.M. Soliman, Y.N. Mabkhot, M.H.M. Al-
Agamy, H.A. Ghabbour, H-K. Fun, Synthesis, Molecular Structure Investigations and Antimicrobial Activity of 2-
Thioxothiazolidin-4-one Derivatives, Journal of Molecular Structure (2014), doi: http://dx.doi.org/10.1016/
j.molstruc.2014.10.038
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Synthesis, Molecular Structure Investigations and
Antimicrobial Activity of 2-Thioxothiazolidin-4-one Derivatives.
Assem Barakata,b,*,†, Hany J. Al-Najjara,†, Abdullah Mohammed Al-Majida,†, Saied M. Solimanb,
Yahia Nasser Mabkhota,†, Mohamed H.M. Al-Agamyc,d,† Hazem A. Ghabboure,†, Hoong-Kun
Fune,f,†
.
aDepartment of Chemistry, College of Science, King Saud University, P. O. Box 2455,
Riyadh-11451, Saudi Arabia.
bDepartment of Chemistry, Faculty of Science, Alexandria University, P.O. Box426, Ibrahimia, 21321
Alexandria, Egypt.
cMicrobiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
dDivision of Microbiology, Pharmaceutics Department, College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia.
eDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box
2457, Riyadh 11451, Saudi Arabia.
fX-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang, 11800 Malaysia.
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: ambarakat@ksu.edu.sa;
Tel.: +966-1467-5884 (A.B.); Fax: +966-1467-5992 (A.B.).
Received: / Accepted: /Published:
Abstract: A variety of 2-thioxothiazolidin-4-one derivatives were prepared and their in vitro
antimicrobial activities were studied. Most of these compounds showed significant antibacterial
activity specifically against Gram-positive bacteria, among which compounds 4a,e,g, 5b,e,g,h and 6f
exhibit high levels of antimicrobial activity against Bacillus subtilis ATCC 10400 with minimum
inhibitory concentration (MIC) value of 16 µg/mL. All compounds have antifungal activity against

Candida albicans. Unfortunately, however, none of the compounds were active against Gram-negative
bacteria. The chemical structure of 3 was confirmed by X-ray single crystal diffraction technique. DFT
calculations of 3 have been performed on the free C10H7Cl2NO2S2, 3a and the H-bonded
complex,C10H7Cl2NO2S2·H2O,3b to explore the effect of the H-bonding interactions on the geometric
and electronic properties of the studied systems. A small increase in bond length was observed in the
C12-O6 due to the H-bonding interactions between 3a and water molecule. MEP study has been used
to recognize the most reactive sites towards electrophilic and nucleophilic attacks as well as the
possible sites for the H-bonding interactions. The TD-DFT calculations have been used to predict
theoretically the electronic spectra of the studied compound. The most intense transition band is
predicted at 283.9 nm due to the HOMO-2/HOMO-1 to LUMO transitions. NBO analyses were carried
out to investigate the stabilization energy of the various intramolecular charge transfer interactions
within the studied molecules.
Keywords: Rhodanine; 2-Thioxothiazolidin-4-one; Anti-microbial activity; X-Ray, DFT, MEP,
TD-DFT, NBO.
Introduction
The treatment of infectious diseases still remains an important and challenging problem. The
extensive search of novel antimicrobial agents is a current field of growing interest. Many compounds
have been synthesized with this aim but their clinical use has been limited by their relatively high risk
of toxicity, ineffectiveness, bacterial resistance and/or pharmacokinetic deficiencies. Infectious
diseases are responsible for a significant proportion of deaths worldwide according to WHO. With all
of these in mind, there is an urgent need for the discovery or optimization of novel antimicrobial
agents that are active against these resistant strains [1]. The diversity in the biological response of 4-
thiazolidinones has attracted the attention of many researchers to explore this framework for its
potential. The 4-thiazolidinone ring system is a core structure in various synthetic pharmaceuticals
displaying a broad spectrum of biological activity, such as antiviral, anti-inflammatory, anticonvulsant,
anti-proliferative, anti-diabetic, cardiovascular, anti-tubercular, anti-hyperlipidemic, antibacterial, and

antifungal properties. Compounds such as pioglitazone (hypoglycemic), etozoline (antihypertensive),
ralitoline (anti-convulsant), and thiazolidomycin (activity against streptomyces species), based on this
pharmacophore are already in the market (Figure 1). In recent years, 4-thiazolidinone derivatives with
antitumor activity on melanoma, leukemia, colon, lung, ovarian, CNS, renal, breast and prostate
cancers cell lines have become a promising area of research. Different researchers have reviewed the
progress on the scaffold from time to time, such as Jain et al. in 2012 [2], Hamama et al. in 2008 [3],
Verma et al. in 2008 [4], Abdel-Rahman et al. in 2001 [5], Singh et al. in 1981 [6], and our group has
also been continuously involved in researching this nucleus through chemical modifications with
encouraging results [7].
Indeed, 4-thiazolidinones have many interesting activity profiles including non-nucleoside inhibitors of
HIV-RT [8], namely COX-1 inhibitors [9], antidiabetic [10], inhibitors of aldose reductase [11-12],
inhibitors of the bacterial enzyme MurB which is a precursor acting during the biosynthesis of
peptidoglycan and YycG histidine kinase [13-14]. Moreover derivatives of 4-thiazolidinones have
been reported for anthelmintic, antitubercular and antifungal activities [15].
Fig1. Some biologically important thiazolidinone compounds.
Thiazolidinones with C-2 and N-3 substituted positions possess diverse degrees of inhibition against
bacteria and fungi. The SAR studies of thiazolidinone derivatives showed that they are more effective
on gram-negative bacteria as compared to gram-positive bacteria. The search for new antimicrobial
agents will continuously remain as an important and challenging task for medicinal chemists. With this
in mind and as part of our ongoing studies towards the development of new antimicrobial agents, the

various structural modifications in the series of synthesized compounds were evaluated against a
variety of pathogens for their antibacterial and antifungal activity. DFT calculations have also been
performed to simulate the effect of H-bonding interactions on the molecular structure and electronic
properties of the investigated systems. TD-DFT calculations were used to predict the accurate
electronic transitions and to draw the HOMO and LUMO levels. The natural bond orbital (NBO)
calculations were used to predict the stabilization energies due to intramolecular charge transfer (ICT)
within the studied systems.
Experimental
Materials and methods
All the chemicals were purchased from Sigma-Aldrich, Fluka etc, and were used without further
purification, unless otherwise stated. Melting point was measured on a Gallenkamp melting point
apparatus in open glass capillaries and is uncorrected. IR Spectra were measured as KBr pellets on a
Nicolet 6700 FT-IR spectrophotometer. The NMR spectra were recorded on a Jeol-400 NMR
spectrometer.
1H-NMR (400 MHz), and 13C-NMR (100 MHz) were run in deuterated
dimethylsulphoxide (DMSO-d6). Chemical shifts (δ) are referred in terms of ppm and J -coupling
constants are given in Hz. Mass spectra were recorded on a Jeol of JMS-600 H. Elemental analysis
was carried out on Elmer 2400 Elemental Analyzer; CHN mode.
Synthesis of 5-((2,4-dichlorophenyl)(hydroxy)methyl)-2-thioxothiazolidin-4-one (3)
A mixture of 2,4-dichlorobenzaldehyde (3 mmol, 525 mg), 2-thioxothiazolidin-4-one 1 (3 mmol,
400mg), and diethylamine (3 mmol, 310μl) in 3 mL of degassed H2O was stirred at room temperature
for 30 mins, the crude product was extracted with mixture of DCM/EtOH, was with 10%HCl
(2*10mL), the organic phase was with brine and recrystallized from DCM/EtOH to afford 3 yellow
o
crystalline material (0.8 g, 2.6 mmol, 87%). m.p: 80 C; IR (KBr, cm–1): 3450, 3015, 1744, 1350;1H-
NMR (400 MHz, DMSO-d6): δ 8.35 (bs, 1H, NH), 7.70(s, 1H, Ph), 7.60- 7.25(m, 4H, CH&CH&
Ph);13C-NMR (100 MHz, DMSO-d6): δ = 198.1, 177.8, 136.1, 134.9, 133.7, 131.6, 129.8, 128.2, 67.1,

65.1; LC/MS (ESI): 309 [M]+; Anal. for C10H7Cl2NO2S2; calcd: C, 38.97; H, 2.29; Cl, 23.01; N,
4.54;Found: C, 39.01; H, 2.31; Cl, 23.12; N, 4.57.
Antimicrobial activity
Chemical compounds were individually tested against a panel of gram positive and negative
bacterial pathogens. Antimicrobial tests were carried out by the agar well diffusion method [16-18]
using 100 mL of suspension containing 1 x 108 CFU/mL of pathological tested bacteria, 1 x 106
CFU/mL of yeast and 1 x 104 spore/mL of fungi spread on nutrient agar (NA), Sabourand dextrose
agar (SDA), and potato dextrose agar (PDA) medium respectively. After the media had cooled and
solidified, wells (10 mm in diameter) were made in the solidified agar and loaded with 100 mL of
tested compound solution prepared by dissolving 100 mg of the chemical compound in one mL of
o
dimethyl sulfoxide (DMSO). The inculcated plates were then incubated for 24 h at 37 C for bacteria
and 48 h at 28 oC for fungi. Negative controls were prepared using DMSO employed for dissolving the
tested compound. Ciprofloxacin (50 mg/mL) and Ketoconazole (50 mg/mL) were used as standard for
antibacterial and antifungal activity respectively. After incubation time, antimicrobial activity was
evaluated by measuring the zone of inhibition against the test organisms and compared with that of the
standard. The observed zone of inhibition is presented in Table 1. Antimicrobial activities were
expressed as inhibition diameter zones in millimeters (mm) as follows: N.A. (no activity) ≤ 4 mm; +
(weak) = 5-9 mm; ++ (moderate) =10-15 mm; +++ (strong) =16-20 mm and ++++ (very strong) ≥ 21
mm. The experiment was carried out in triplicate and the average zone of inhibition was calculated.
Determination of MIC for active compounds
MIC of the 19 compounds and two standard controls (ciprofloxacin and itraconazole) were performed
by microbroth dilution method as proposed by European Committee on Antimicrobial Susceptibility
Testing (EUCAST, 2014). Briefly, the compounds were dissolved in dimethylsulphoxide to give final
concentration 1024 mg/mL, and then two fold dilutions were made in the 2X Mueller-Hinton broth
(Oxoid Chemical Co. UK) for antibacterial and in 2X RPMI broth for antifungal activity, to give final
concentration 512 mg/mL. A 50 μL of broth was dispensed into wells of sterile 96 microtitre plate. A

50 μL of the tested compounds (512 mg/μL) was pipetted into the wells in first well and mixed the
contents by using multipippetor by pipetting up and down 6 to 8 times. Then 50 μL from the first
column was withdrawn and added to the second well to make a twofold dilution. This procedure was
repeated down to 12th well to reach the concentration of 0.25 μg/mL. A 50 μL was discarding from
12th well. Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 2912 and Bacillus
subtilis ATCC 1040 were grown in the tryptone soy broth to the right A560. However Candida
albicans ATCC 2091 was grown in Sabouraud dextrose broth to the right A530. A 100 μL of bacterial
inoculums (1X105-1X106 CFU/mL) was dispensed into wells to give final bacterial inocula was
0
0.5X105-0.5X106 CFU/mL. The microtiter plates were incubated at 35 C for 18 h. After the
incubation period, the results of MIC were recorded manually and interpreted according to the
recommendations of EUCAST. MIC is defined as the highest dilution of the drug that kills or inhibits
the visible growth of microorganism.
Molecular modeling
All the modeling studies were carried out on a desktop PC, Intel® Core ™ 2 Duo CPU E8200 @
2.66 GHz, RAM 4 GB operating under Windows 7 professional. It consists of several steps. First, the
3D crystal structures of MurB with PDB code 2Q85 was downloaded from Brookhaven protein data
bank (PDB;http://www.rcsb.org/pdb) loaded to Molegro Virtual Docker (MVD 2013.6.0.0 [win32])
program fully functional free trial version with time limiting license [19,20]. All the atom types,
charges and bond hybridization were carefully checked. The MolDock Score [GRID] and MolDock
Optimizer routines as implemented in Molegro Virtual Docker (MVD version 2013.6.0.0). The non-
bonded oxygen atoms of waters, present in the crystal structure were removed. ChemBio3D Ultra 105
was used to draw the 3D structures of different ligands. Ligands were further pre-optimized using free
6
version of Marvinsketch 4.1.13 from Chemaxon Ltd with MM force field and saved in Tripos mol2
file format. MolDock score functions were used with a 0.3 Å grid resolution. Prior to the calculations
of the subject compounds, the MVD software was benchmarked docking the naphthyl tetronic acid
inhibitor.

Results and Discussion
Chemistry
The synthetic strategies adopted to obtain the target compounds are depicted in scheme 1. The 2-
thioxothiazolidin-4-one derivatives were synthesized by the literature procedure described by Barakat,
et al[7]. 2-Thioxothiazolidin-4-one derivatives were prepared by condensing the 2-thioxothiazolidin-4-
one with various aldehyde in the presence of aqueous diethylamine medium to yield the Aldol products
with subsequently addition of thiol to obtain thia-Michael adducts. The three-component one pot
aqueous diethylamine-promoted synthesis of these target molecules provides an environment friendly
and benign synthesis with rapid and easy access to 2-thioxothiazolidin-4-one compounds in good to
excellent yields.
Scheme 1. Synthesis of 2-thioxothiazolidin-4-one derivatives by Aldol-thia-Michael reaction in
aqueous diethylamine.

H
N
N
H
H
N
H
S
O
N
N
N
N
HS
O
N
HS
O
HS
O
HS
S
O
O
S
S
O
S
S
OH
S
S
S
Cl
S
NH
N
S
O
Cl
3
4a
4b
4c
4d
4e
4f
N
H
H
N
N
N
N
N
H
H
N
N
H
H
N
H
H
H
H
H
H
N
N
S
O
S
O
S
O
N
S
O
S
O
S
O
S
S
S
S
S
S
S
S
S
S
S
Ph
Ph
Ph
Ph
Ph
H C
3
Cl
5b
Br
4g
5a
5c
5d
5e
N
H
H
N
N
N
H
H
N
N
H
H
H
H
H
N
N
N
S
O
S
O
S
O
S
O
S
O
S
S
S
S
S
S
S
S
S
S
H C
3
Cl
Ph
Ph
Ph
Ph
Ph
CH
3
H C
3
Cl
H CO
3
5f
5g
5h
5i
6a
H
N
H
H
H
N
H
N
N
S
O
N
S
O
S
O
S
O
S
O
S
S
S
S
S
S
S
S
S
S
Cl
Ph
Ph
Ph
Cl
Ph
Ph
Br
6c
Cl
6b
6d
6e
6f
1
The structures of these compounds were characterized by H NMR, 13C NMR, MS, IR, elemental
analysis, and X-ray diffraction crystallography in a similar manner as those earlier compounds that
have been fully reported by our group [7].
Single crystal X-ray diffraction analysis of compound of 3
Interestingly, the Aldol intermediate 3can be separated by stopping the reaction after 0.5h and the
product was unambiguously elucidated by X-ray diffraction analysis.

The structure of 3 (Fig. 2) was confirmed by X-ray crystal structure analysis. CCDC- 989933 contains
the supplementary crystallographic data for this compound. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.
Fig 2: ORTEP diagram of the structure of 3
A clear intense yellow block-like specimen of C10H7Cl2NO2S2·H2O, approximate dimensions
0.301 mm x 0.420 mm x 0.580 mm, was used for the X-ray crystallographic analysis. A total of 630
frames were collected by Bruker APEX-II D8 Venture. The frames were integrated with the Bruker
SAINT software package using a narrow-frame algorithm [21-22] The integration of the data using a
triclinic unit cell yielded a total of 54109 reflections to a maximum θ angle of 30.71° (0.70 Å
resolution), of which 8093 were independent (average redundancy 6.686, completeness = 98.8%, Rint =
7.05%, Rsig = 4.84%) and 6001 (74.15%) were greater than 2σ(F2). The final cell constants of a =
9.0528(11) Å, b = 10.6637(13) Å, c = 14.8063(18) Å, α = 85.702(4)°, β = 75.933(4)°, γ = 72.013(4)°,
volume = 1318.7(3) Å3, are based upon the refinement of the XYZ-centroids of 9768 reflections above
20 σ(I) with 4.863° < 2θ < 61.11°. Data were corrected for absorption effects using the multi-scan
method (SADABS). The ratio of minimum to maximum apparent transmission was 0.872. The
calculated minimum and maximum transmission coefficients (based on crystal size) are 0.6520 and
0.7930.

The final anisotropic full-matrix least-squares refinement on F2 with 357 variables converged at R1 =
4.72%, for the observed data and wR2 = 12.59% for all data. The goodness-of-fit was 1.021. The
largest peak in the final difference electron density synthesis was 0.843 e-/Å3 and the largest hole was -
0.398 e-/Å3 with an RMS deviation of 0.117 e-/Å3. On the basis of the final model, the calculated
density was 1.643 g/cm3 and F(000), 664 e-.
The asymmetric unit contains two molecules of the compound and two water molecules with disorder
in the hydrogen atoms (Fig. 2). The molecular structure of compound 3 is composed of a thiazole ring
(S1/C1/N1/C2-C3) which is linked to a phenyl ring (C5-C10) through C4. The thiazole ring forms a
dihedral angle of 41.88 (3)° with the adjacent benzene ring. The molecule is bent (Fig. 2) at the C4
atom with a S1A–C3A–C4A–C5A torsion angle of −58.1 (2)° and S1B—C3B—C4B—C5B torsion
angle of −63.9 (2) °. In the crystal structure intermolecular O–H⋅⋅⋅O and N–H⋅⋅⋅O hydrogen bonds are
observed (Fig.3 and Table 1)
Fig3. Crystal packing showing intermolecular O–H⋅⋅⋅O and N–H⋅⋅⋅O hydrogen bonds as dashed lines.
Table 1.
Hydrogen bond parameters for 3
D—H···A
D—H
H···A
D···A
D—H···A
O1WA—H1WA···O2A
0.8200
1.9300
2.738 (2)
168.00

O1WA—H3WA···O1WB
O1WB—H1WB···O2B
O1WB—H2WB···O1WA
N1A—H1NA···O1WBi
N1B—H1NB···O1WAii
O2A—H1OA···O1Biii
O2B—H1OB···O1Aiv
C10A—H10A···O2A
C10B—H10B···O2B
0.8900
1.8100
2.703 (3)
2.763 (2)
2.703 (3)
2.783 (3)
2.755 (3)
2.732 (3)
2.766 (3)
2.739 (3)
2.758 (3)
173.00
0.8000
1.9800
167.00
0.7500
1.9500
173.00
0.82 (3)
0.83 (3)
0.84 (3)
0.81 (3)
0.9300
2.01 (3)
1.96 (3)
1.90 (3)
1.97 (3)
2.3900
157 (3)
160 (3)
175 (4)
166 (3)
102.00
0.9300
2.4200
101.00
Symmetry codes: (i)−x+2, −y+1, −z+1; (ii) −x+1, −y+1, −z+1; (iii) x+1, y, z; (iv) x−1, y, z.
Computational details
All the quantum chemical calculations of the C10H7Cl2NO2S2, 3a and its H-bonded complex
C10H7Cl2NO2S2·H2O, 3b were performed by applying DFT method with the B3LYP functional and 6-
311G(d,p) basis set using Gaussian 03 software [23]. The input files were taken from the CIF file
obtained from our reported X-ray single crystal measurements. The geometries were optimized by
minimizing the energies with respect to all the geometrical parameters without imposing any molecular
symmetry constraints. GaussView4.1 has been used to draw the structures of the optimized geometries
[24]. Frequency calculations at the optimized geometry were done to confirm the optimized structures
to be an energy minimum. The true energy minimum at the optimized geometry of the studied
compounds was confirmed by absence of any imaginary frequency modes. The possible electronic
transitions of 3b were calculated by the TD-DFT method. The natural bond orbital analyses were
performed using the NBO calculations as implemented in the Gaussian 03 package [25] at the
DFT/B3LYP level.

Molecular Geometry
The optimized bond lengths and bond angles obtained for the studied compounds using the B3LYP
method with 6-311G(d,p) basis set are given in Table 2; while the atom numbering of the optimized
structures are given in Fig. 4. Both molecules possesses C1 point group. The optimized geometry of 3b
is compared with the structural parameters obtained from the CIF file. Generally, the bond lengths and
bond angles are predicted very well. Most of bond lengths are overestimated except C5-O9 bond. The
maximum deviations of the calculated bond length and bond angle values from the experimental data
are 0.028Å (C10-S1) and 2.416° (C12-C10-S1) respectively. These deviations are attributed to the
phase difference between the calculations and the experiment. The calculations refer to an isolated
molecule in the gas phase, while the experimental data are those for the molecule in the solid phase.
The experimental values of C-C-C angles for benzene ring are around the typical hexagonal angle of
120° [26]. The calculated C-C-C bond angles values are in the range of 118.54-122.27° (exp. 118.25-
122.37°). A comparison between the calculated geometric parameters of 3a and 3b is shown in Fig.5
and Table 2. The effect of H-bonding interactions between 3a and water molecule seems to be
insignificant. There is small increase for the C12-O6 bond length due to H-bonding interactions with
the water molecule. The rest of the geometric parameters are affected very little.
3a
3b
Fig. 4 The optimized molecular structures of the studied compounds 3a,b.
Table 2.

Comparative experimental and calculated bond distances (Å) and bond angles (º) of the studied
compound.
DFT
DFT
Parametera
X-ray
Parametera
X-ray
3a
3b
3a
3b
R(1-8)
R(1-10)
R(2-8)
R(3-15)
R(4-18)
R(5-9)
R(6-12)
R(6-24)
R(7-8)
1.764
1.842
1.640
1.765
1.754
1.208
1.418
0.963
1.379
1.382
1.013
1.527
1.092
1.553
1.095
1.516
1.398
1.398
1.391
1.081
1.389
1.390
1.082
1.390
1.081
93.31
1.766
1.843
1.637
1.765
1.754
1.209
1.427
0.964
1.382
1.380
1.013
1.528
1.093
1.549
1.094
1.515
1.400
1.399
1.390
1.081
1.389
1.389
1.082
1.390
1.083
93.09
1.747 A(3-15-16)
1.815 A(4-18-16)
1.627 A(4-18-19)
1.750 A(5-9-7)
1.744 A(5-9-10)
1.222 A(12-6-24)
1.425 A(6-12-10)
0.813 A(6-12-13)
1.374 A(6-12-14)
1.354 A(8-7-9)
0.827 A(8-7-23)
1.513 A(9-7-23)
0.979 A(7-9-10)
1.545 A(9-10-11)
0.980 A(9-10-12)
1.506 A(11-10-12) 109.19 108.59 109.29
1.401 A(10-12-13) 105.37 105.42 108.47
1.392 A(10-12-14) 112.37 112.57 111.84
1.383 A(13-12-14) 109.07 108.92 108.49
0.929 A(12-14-15) 122.66 121.60 121.53
1.378 A(12-14-21) 119.99 121.03 121.57
1.388 A(15-14-21) 117.35 117.37 116.89
0.931 A(14-15-16) 122.19 122.27 122.37
1.384 A(14-21-19) 121.74 121.50 122.31
0.930 A(14-21-22) 118.19 119.69 118.84
93.10 A(15-16-17) 120.48 120.47 120.89
117.22 117.06 117.99
119.09 119.07 118.85
119.81 119.89 119.23
124.66 124.86 125.39
124.56 124.47 122.71
107.79 107.19 104.89
110.52 110.74 109.59
110.38 108.96 108.53
109.08 110.07 109.85
119.81 119.71 118.77
119.62 119.54 120.52
120.28 120.38 120.55
110.76 110.66 111.88
108.07 107.90 109.29
109.61 110.02 109.06
R(7-9)
R(7-23)
R(9-10)
R(10-11)
R(10-12)
R(12-13)
R(12-14)
R(14-15)
R(14-21)
R(15-16)
R(16-17)
R(16-18)
R(18-19)
R(19-20)
R(19-21)
R(21-22)
A(8-1-10)
A(1-8-2)
A(1-8-7)
A(1-10-9)
125.09 125.15 124.79 A(15-16-18) 118.57 118.54 118.25
109.62 109.59 110.15 A(17-16-18) 120.95 120.99 120.86
106.06 106.00 106.10 A(16-18-19) 121.10 121.04 121.92
A(1-10-11) 108.18 107.95 109.33 A(18-19-20) 120.26 120.35 120.83
A(1-10-12) 115.48 116.09 113.67 A(18-19-21) 119.05 119.29 118.24
A(2-8-7)
125.29 125.26 125.06 A(20-19-21) 120.69 120.36 120.93
A(3-15-14) 120.58 120.67 119.64 A(19-21-22) 120.07 118.81 118.85
a Atom numbering referred to Fig. 4
Natural Atomic Charges
The natural atomic charges (NAC) at the different atomic sites of 3a and 3b calculated using the
DFT/B3LYP method are collected in Table 3. All the hydrogen atoms are electropositive. For 3a, the
most positive H-sites are H23 (+0.4290) and H24 (+0.4739). In contrast, the C-atoms have negative
charge densities except C9, C12 and C15. The most positive C-site is C12 as it lies between the two
strong electronegative O and N atoms. Similar observations are obtained for 3b. Moreover, the O6 and
O25 have the highest negative charge density for 3a and 3b respectively. The NAC values at all atomic
sites are affected very little due to the interaction between 3a and the water molecule. The largest

variation of the NAC values due to H-bonding interaction with the water molecule occurs at O6. The
negative charge density at this atomic site is increased from -0.7419 in case of 3a to -0.7665 for 3b.
Table 3.
The calculated natural atomic charge values of the studied molecules
Atom
3a
3b
S1
S2
Cl3
Cl4
0.3379
-0.0466
-0.0065
0.0079
-0.5778
-0.7419
-0.6213
-0.1183
0.7091
-0.4223
0.2527
0.1361
0.2107
-0.0975
0.0054
-0.2527
0.2369
-0.0015
-0.2199
0.2248
-0.1561
0.2379
0.4290
0.4739
0.3413
-0.0312
-0.0071
0.0095
-0.5830
-0.7665
-0.6211
-0.1229
0.7082
-0.4233
0.2537
0.1380
0.2139
-0.1033
0.0069
-0.2534
0.2372
-0.0003
-0.2173
0.2267
-0.1648
0.2433
0.4300
0.4817
-0.9064
0.4681
0.4423
O5
O6a
N7
C8
C9
C10
H11
C12
H13
C14
C15
C16
H17
C18
C19
H20
C21
H22
H23
H24
O25
H26
H27
a Largest NAC variation

1.9
1.8
1.7
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
Compound 1
Compound 2
Parameter
Fig.5 Comparison between the calculated bond distances of 3a and 3b.
Molecular electrostatic Potential (MEP)
The molecular electrostatic potential (MEP) is a useful property for predicting sites and relative
reactivities towards electrophilic and nucleophilic attack and in the studies of hydrogen bonding
interactions [27,28]. The MEP of 3a and 3b calculated using B3LYP with 6-311G(d,p) basis set is
used to predict the reactive sites for electrophilic and nucleophilic attack. The negative (red) regions of
the MEP are related to electrophilic reactivity and the positive (blue) regions to nucleophilic reactivity,
as shown in Fig. 6. It can be seen from this figure that, negative regions are mainly localized over the
O5 and O25 atoms. These sites present the most reactive sites for electrophilic attack and are the most
H-acceptor sites for making H-bonding interactions. The maximum positive regions are localized on
the H23, H24, H25 and H27 atoms which represent the most reactive sites for nucleophilic attack as
well as for being the H-donor sites for the H-bonding interactions. These results agree with our
reported X-ray structure of the studied compound.

Fig. 6 Molecular Electrostatic potentials (MEP) mapped on the electron density surface calculated by
the DFT/B3LYP method.
Electronic absorption spectra and frontier molecular orbitals (FMOs)
The frontier molecular orbitals can offer a reasonable qualitative indication on the excitation properties
and the ability of the molecule towards electron transport process [29, 30]. The HOMO and LUMO
energies of 3bwere investigated using the DFT/B3LYP method. Fig. 7 shows the isodensity surface
plots of HOMO and LUMO. It can be seen from Fig. 7 that the electron densities of HOMO and
LUMO are mainly localized on the thiazole ring. The EHOMO, ELUMO and transition energies (ΔE) for
3b are calculated to be -6.8097eV, -2.4324eV and 4.37726eV respectively. In order to understand the
accurate electronic transitions of the titled compound, 3b, the first twenty spin allowed singlet-singlet
excitations were calculated using TD-DFT. The results are shown in Table 4 which represents the
calculated λ
values and the oscillator strength (f) of these transition bands with their major
max
contributions of molecular orbitals. Of these electronic transitions obtained from the current
calculations, the most intense transition band is calculated at 283.9 nm corresponds to the electronic
transitions from the HOMO-2/HOMO-1 to LUMO.

EHOMO=-6.8097eV
ELUMO=-2.4324eV
ΔE=4.37726eV
Fig. 7 The ground state isodensity surface plots for the frontier molecular of 3b.
Table 4.
The calculated electronic spectra of 3b using the TD-DFT method
λ
max
fosc
Major contribution
λ
max
fosc
Major contribution
394.3 0.0003 H→L (93%)
236.6 0.0056 H-4→L (89%)
283.9 0.2024 H-2→L (15%), H-1→L (68%)
277.3 0.0335 H-2→L (77%)
231.1 0.0054 H-2→L+2 (15%), H-1→L+2 (76%)
229.7 0.0267 H-5→L (11%), H→L+3 (65%)
226.3 0.0322 H→L+4 (50%), H→L+5 (35%)
H-1→L+1 (15%), H-1→L+3 (47%),
257.8 0.0084 H-3→L (90%)
256.9 0.0032 H→L+1 (77%), H→L+3 (10%) 225.0 0.0185 H-1→L+5 (14%)
248.7 0.0115 H-6→L (73%) 221.9 0.1243 H-3→L+2 (11%), H-2→L+1 (61%)
H-3→L+1 (17%), H-2→L+2 H-2→L+4 (13%), H-1→L+3 (14%),
245.7 0.0013 (22%), H→L+2 (36%) 212.8 0.0144 H-1→L+4 (48%)
H-2→L+2 (12%), H-1→L+1 H-2→L+4 (40%), H-1→L+3 (13%),
212.2 0.0025 H-1→L+5 (22%)
210.5 0.0005 H-8→L (38%), H-7→L (56%)
243.4 0.0085 (10%), H→L+2 (61%)
242.2 0.0055 H-1→L+1 (59%)
237.8 0.1168 H-5→L (53%), H→L+3 (14%) 207.7 0.0046 H→L+4 (40%), H→L+5 (50%)
Natural bond orbital (NBO) analysis

A useful aspect of the NBO method is that it gives information about the intra- and intermolecular
interactions. Delocalization of electron density between occupied Lewis-type (bond or lone pair) NBO
orbitals and formally unoccupied NBO orbitals correspond to a stabilizing donor–acceptor interaction.
The larger the interaction energies (E(2)) value, the more intensive is the interaction between electron
donors and electron acceptors, i.e. the more donating tendency from electron donors to electron
acceptors and the greater the extent of conjugation of the whole system [31].
NBO analysis has been performed on the studied molecules at the B3LYP/6-311G(d,p) level in order
to elucidate the delocalization of electron density within the molecule. The energy of these interactions
(E(2)) can be estimated by the second-order perturbation theory [32]. The stabilization energies(E(2))
obtained from the second order perturbation theory for compounds 3aand 3bare reported in Table 5.
The intramolecular charge transfer (ICT) interaction is formed by the orbital overlap between π(C C)
and π* (C-C) bond orbitals causing stabilization of the system upto 96.34kJ/mol. The most important
interaction energy in the studied molecules, is electron donating from LP(1)N7 to the antibonding
π*(S2-C8) and π*(O5-C9) NBOs resulting in maximum stabilization upto 263.89 kJ/mol. The
LP(1)O6→σ*(O25-H26) and LP(2)O25→σ*(C21-H22) intramolecular charge transfer interactions
clearly manifests the evidences of the intramolecular H-bonding interactions. The interaction energies
(E(2)) due to these ICT were calculated to be 10.38 and 16.08 kJ/mol respectively. The stronger O-
H…O H-bonds further stabilizes the system more than the weaker C-H…O interactions.
Table 5.
The stabilization energies E(2) (kJ/mol) of the most important charge transfer interactions in the studied
compounds using B3LYP method.
E(2) kJ/mol
E(2) kJ/mol
Donor NBO (i)
Acceptor NBO (j)
3a
3b
π(C14-C15) π*(C16-C18)
π(C14-C15) π*(C19-C21)
π(C16-C18) π*(C14-C15)
π(C16-C18) π*(C19-C21)
π(C19-C21) π*(C14-C15)
π(C19-C21) π*(C16-C18)
85.41
84.24
77.12
80.76
77.71
91.10
95.04
166.89
64.94
57.40
51.08
76.83
82.31
77.37
91.57
96.34
161.69
65.82
58.20
51.25
LP(2)S1
LP(2)S2
LP(2)S2
LP(3)Cl3
π *(S2-C8)
σ*(S1-C8)
σ*(N7-C8)
π *(C14-C15)

LP(3)Cl4
LP(2)O5
LP(2)O5
LP(2)O6
LP(1)N7
LP(1)N7
LP(1)O6
LP(2)O25
π *(C16-C18)
σ*(N7-C9)
σ *(C9-C10)
σ *(C10-C12)
π*(S2-C8)
π*(O5-C9)
σ *(O25-H26)
σ *(C21-H22)
54.14
113.59
89.97
38.81
263.98
195.86
54.47
112.50
89.72
32.74
255.48
190.54
16.08
10.38
Antimicrobial assay
Anti-bacterial activity studies
The antimicrobial activity and the Minimum Inhibitory Concentration (MIC) were performed by cup
plate method and microbroth dilution method respectively with different strains [16-18].
The prepared compounds were screened for their antibacterial activity against Gram-positive bacteria
(Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC 10400 and Enterococcus faecalis
ATCC 2912) and Gram-negative bacteria (Pseudomonas aeruginosa ATCC 27853, Proteus vulgaris
ATCC 6380, Klebsiella pneumoniae ATCC 27736, and Escherichia coli ATCC 25218). Briefly, 50 μL
of 2xMueller-Hinton broth (Oxoid Chemical Co. UK) was dispensed into wells of sterile 96 microtitre
plate. A 50 μL of the tested compounds (512 mg/μL) was pipetted into the wells in first well and
mixed the contents by using multipippetor by pipetting up and down 6 to 8 times. Then 50 μL from the
first column was withdrawn and added to the second well to make a twofold dilution. This procedure
was repeated down to 12th well to reach the concentration of 0.25 μg/mL. A 50 μL was discarding
from 12th well. The tested organisms were grown to mid-log phase in Mueller-Hinton broth to the
right A560and diluted 100-fold in the same medium to obtain 1X105-1X106 CFU/mL. Ciprofloxacin
wasused as positive controls for bacteria. A 100 μL of bacterial inoculums (1X105-1X106 CFU/mL)
was dispensed into wells to give final bacterial inocula was 0.5X105-0.5X106 CFU/mL. The microtiter
plates were incubated at 35 0C for 18 h. After the incubation period, the results of MIC were recorded
manually and interpreted according to the recommendations of EUCAST. The MIC (expressed in
μg/mL) was the lowest concentration of the test substance that completely inhibited growth of the
microorganism. The results of antibacterial activity of the compounds are summarized in Table 6. The

tested compounds were specifically active against Gram-positive bacteria (Staphylococcus auerus,
Bacillus subtilis, and Enterococcus faecalis). All examined derivatives were inactive against Gram-
negative rods (data not shown).
Compounds 3, 4a,e,g,f, 5a,b,d,e,g,h,I and 6b-f possessed good activity against tested Gram-positive
Staphylococcus auerus., in comparison with the reference compound Ciprofloxacin. For most bacterial
strains tested the MIC values of compounds 3, 4a,e,g,f, 5a,b,d,e,g,h,I and 6b-f were between 32 and
64 μg/mL.
All compounds 3, 4a,c,e,g,5a,b,d,e, and 6a-f showed MIC values in the range of 16–128 μg/mL
against B. subtilis bacteria and E. faecalis (Table 6). Graphical representation of MIC (μg/mL) of
compounds (3-6) against bacterial strains (Figure 8).
The results of antibacterial activity (Table 6) revealed that among all compounds, 4a,e, 5a,e,g-i and 6f
were found to be most active against Gram-positive bacteria MIC value of 16 μg/mL with diameter of
growth of inhibition zone of ≥21 mm.
In vitro Antifungal activity
Antifungal activity of all compounds (3–6) was evaluated by selecting one yeast strain Candida
albicans ATCC 2091 on the basis of their clinical importance and MIC was determined [18]. The
diameter of growth of inhibition zone (mm) and MIC (μg/mL) of all compounds was determined using
itraconazole as a standard drug. The results of antifungal activity of all compounds (3–6) are shown in
Table 6. It can be seen from Table 6 that all compounds showed good antifungal activity. The diameter
of growth of inhibition zone was observed in the range of 5-20 mm and MIC in the range of 32–
64 μg/mL for yeast C. albicans ATCC 2091 for compounds 3–6.
Table 6.
Antimicrobial activity of 2-thioxothiazolidin-4-one derivatives (3-6).
GRAM-POSTIVE BACTERIA
Fungi
Comp.
No.
Staphylococcus aureus
Candida
albicans
#
Bacillus subtilis
Enterococcus faecalis
ATCC 29213 (COCCI)

ATCC 10400(BACILI)
ATCC2912 ( COCCI)
ATCC2091
Sensitivity
Sensitivity
MIC
Sensitivity
MIC
Sensitivity
MIC
64
MIC
64
1.
2.
3
++
++
++++
N.A.
+
+
++
++
64
16
128
128
ND
4a
4b
4c
4d
4e
4g
4f
+++
N.A.
64
32
3.
N.A.
+
ND
64
ND
ND
4.
++
+
+
++
+
+++
+
128
64
32
5.
N.A.
ND
ND
ND
ND
64
6.
++
++++
++++
+++
+++
++++
+
++
+
++
64
64
32
64
32
16
16
32
32
16
64
128
64
7.
+++
+++
+++
+++
+
++
32
8.
++
+
+++
++
32
9.
5a
5b
5c
5d
5e
5f
32
128
128
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
+
+++
+
32
+
ND
32
ND
ND
ND
+++
++
64
+
128
++
64
+++
++++
+
++
+
+++
+
32
32
16
64
ND
128
64
N.A.
ND
64
ND
ND
5g
5h
5i
++
++
++++
++++
++++
++
16
+
+++
+++
+++
++
32
++
+
32
32
64
32
32
32
64
64
ND
64
16
+++
+
16
32
128
64
6a
6b
6c
6d
6e
6f
64
++
++
++
+
128
64
++
++
+++
+++
+++
++
64
32
32
64
++
+++
+++
+++
++++
++++
64
64
++
64
128
64
++
++
++
++++
64
32
++
16
++
64
64
++++
0. 5
0.25
0.125
24
CI

ND
ND
ND
++++
0.5
25
IT
aAntimicrobial activities were expressed as inhibition diameter zones in millimeters (mm) as follows: N.A. (no activity) < 4
mm; + (weak) = 5-9 mm; ++ (moderate) = 10-15 mm; +++ (strong) = 16-20 mm and ++++ (very strong) ≥21 mm. The
experiment was carried out in triplicate and the average zone of inhibition was calculated. MIC = Minimum Inhibitory
Concentration; MIC expressed in μg/mL; MIC was done by microbroth dilution method according to EUCAST; CI=
Ciprofloxacin; IT= Itraconazole and ND: Not Determine
MIC
140
120
100
80
60
40
20
0
3
4a 4c 4e 4g 4f 5a 5b 5d 5e 5g 5h 5i 6a 6b 6c 6d 6e 6f
St. aureus B. subtilis Ent. Faecalis C. albicans
Fig 8. Graphical representation of MIC (μg/mL) of compounds (3-6) against bacterial strains.
Molecular modeling study
Molecular docking is a very popular method employed to investigate drug interactions. Docking-based
drug design by the use of structural biology remains one of the most logical and esthetically pleasing
approaches in the drug discovery process. MurB enzyme is essential for peptidoglycan biosynthesis in
the bacterial cell wall. The absence of a homologue in eukaryotic cells makes MurB a good target for
small molecule inhibitors with the potential to have antibacterial activity. Biochemical characterization
and X-ray structural analysis of MurB from Escherichia coli were studied before and based on a
cocrystal structure study of E. coli MurB with naphthyl tetronic acid inhibitor (PDB code 2Q85) it was
found that the cocrestallized inhibitor interacts with residues Leu218, Asn233, Pro252, Tyr254 and
Ala264. On other hand, for the carboxylate group of uridine diphosphate N-acetylglucosamine, the
normal substrate of the enzyme interacts with residues Arg159 and Glu325, whereas the diphosphate
moiety of the substrate interacts with residues Tyr190, Lys217, Asn233, and Glu288 [33-34].

To compare the binding affinity of the newly synthesized compounds, they were docked in the
empty binding site of MurB (PDB entry 2Q85).The naphthyl tetronic acid (standard inhibitor) reveals
MolDock score of -113 and forms two hydrogen bonds between its hydroxyl groups on the furan ring
with Gln288 and Asn233 with a bond distance of 2.90 and 3.32 Å, respectively (Figure 9). Compounds
5a-i and 6a-f exhibited MolDock scores ranging from -122 to -103, compared to compounds 3 and 4a-
f which have bad MolDock sores ranging from -87 to -80. Compounds 5h, 5f and 6e have highest
MolDock scores in this study; -122, -117 and -116 respectively. Compound 5h forms two hydrogen
bonds between the oxygen of thiazolidone ring with the guanido group of Arg214 of distances 2.96
and 3.22 Å. The naphthyl moiety was also located in the hydrophobic pocket in the active site (Figure
9). Lipophilicity appears to play crucial role in 5h inhibitory activity, as naphthyl moiety is properly
oriented to the more lipophilic area of the MurB binding site through formation of CH-π interactions.
a)
b)
Fig 9: a) Best pose of the naphthyl tetronic acid (Sticks) with hydrogen bonding to MurB active site.
b) Interactions between compound 5h (Sticks) with an MurB active site. Blue dashes represent H-
bonds.
Conclusions
In conclusion, 4-thiazolidinone derivatives were prepared and studied for antimicrobial activity.The
DFT calculations showed that, the interaction between 3 and water molecule has very little effect on its
geometric parameters. Only a slight elongation for the C12-O6 bond has been predicted. The natural

atomic charge density at O6 is shifted to more negative value due to the H-bonding interaction with the
water molecule. MEP map showed that O5 and O25 atoms are the most reactive sites for electrophilic
attack while the H23, H24, H25 and H27 are the most reactive sites for nucleophilic attack. The NBO
calculations showed that, the O H…O and C H…O H-bonding interactions stabilized the system
upto 16.08 kJ/mol. Most of the studies have demonstrated the efficacy of antimicrobial agent in a
particular gram-positive bacteria. All compounds showed good antifungal activity. The docking studies
of compound 5h at the MurB binding site were also performed.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding the work through the research group project Number RGP- VPP- 257.
Author Contributions
Hany Al-Najjar: Carried out the experimental part; Mohamed Al-Agamy carried out the
antimicrobial activity; H. Ghabbour and H-K. Fun carried out the X-ray part; Saied M. Soliman
performed the computational studies; Y. Mabkhot, and A. Al-Majid: helped in the results and
discussion and writing the manuscript; A. Barakat: proposed the subject, and designed the study. All
the authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Graphical Abstract
EHOMO=-6.8097eV
ELUMO=-2.4324eV
ΔE=4.37726eV
Highlights
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A series of 2-thioxothiazolidin-4-onederivatives have been synthesized.
The structure for 3 was elucidated by X-ray diffraction.
MEP, NBO and FMO were studied using DFT calculations.
In-vitro evaluation of antibacterial and antifungal potencies were carried out.