Synthesis, crystal structure, antimicrobial activity and docking studies of new imidazothiazole derivatives

Article abstract of DOI:10.1007/s13738-019-01766-4

A series of imidazothiazole derivatives were synthesized via Claisen–Schmidt condensation of aldehyde 3, and different methyl ketones and their chemical structures were confirmed using ¹³C NMR, ¹H NMR and LC–MS. In addition, the mole

Full text of DOI:10.1007/s13738-019-01766-4

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01766-4
ORIGINAL PAPER
Synthesis, crystal structure, antimicrobial activity and docking studies
of new imidazothiazole derivatives
M. Koudad1,2 · C. El Hamouti3 · A. Elaatiaoui1,2 · S. Dadou1,2 · A. Oussaid1,2 · F. Abrigach1 · G. Pilet4 · N. Benchat1 ·
M. Allali5
Received: 31 January 2019 / Accepted: 12 August 2019
© Iranian Chemical Society 2019
Abstract
A series of imidazothiazole derivatives were synthesized via Claisen–Schmidt condensation of aldehyde 3, and diferent
methyl ketones and their chemical structures were confrmed using 13C NMR, 1H NMR and LC–MS. In addition, the molecu-
lar structure of compound 3 was defned by single-crystal X-ray difraction. The antibacterial and antifungal activities of
synthesized compounds were investigated by difusion method against three pathogenic bacteria (Pseudomonas aeruginosa,
Escherichia coli and Staphylococcus aureus) and one pathogenic fungus (Fusarium oxysporum). Compound 3 displayed
signifcant antibacterial activity against E. coli and P. aeruginosa (MIC≤0.2 mg/ml). Concerning the antifungal activity,
all the molecules show very interesting results versus F. oxysporum (IC50 ≤0.07 mg/ml). These results were confrmed by
the molecular docking studies such as some compounds showing optimum binding energy and afnity to the active site of
the receptor.
Keywords Imidazothiazole · Antibacterial · Antifungal · Molecular docking
Introduction
because of the nitrogen-containing heterocyclic ring (present
in natural products like histidine, biotin, nucleic acid, purine,
etc.) and exhibit a wide spectrum of biological activity and
pharmacological diversity, such as inhibition of some spe-
cifc enzymes, anthelmintic [1], anti-infammatory [2], anti-
bacterial [2], fungistatic [3], antioxidant [4] and anticancer
[5, 6]. Many studies report favorable biological properties of
the imidazo[2,1-b]thiazole derivatives, especially anticancer
activity against diferent kinds of human cancer cells [5,
6]. Among these active imidazo[2,1-b]thiazole derivatives
are the immunomodulator and anthelmintic agent levami-
sole 1 and the anticancer agent YM-201627 2a (Scheme 1),
an N,N-diethyl-2-(3-imidazo[2,1-b] [1, 3] benzothiazol-
2-ylphenoxy)ethanamine dihydrochloride [6, 7]. The
imidazo[2,1-b]thiazol-naphthamide 2b (Scheme 1) has been
described as a SIRT1-activating compound [8, 9]. In the
last years, various derivatives of thiazole and imidazo[2,1-b]
benzothiazole have been developed and described as hav-
ing anticancer activity such as 3,6-diphenylimidazo[2,1-b]
thiazole derivatives (2c) [10–12] (Scheme 1).
Recently, the fused heterobicyclic systems containing
bridgehead nitrogen atom fnd an enormous importance in
medicinal chemistry and health because of their interest-
ing chemical, biological and pharmacological properties.
Indeed, imidazothiazole derivatives are especially attractive
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01766-4) contains
supplementary material, which is available to authorized users.
* M. Allali
mallali.ispits.fes@gmail.com
1
LCAE, Faculty of Sciences, University Mohammed Premier,
Oujda, Morocco
2
Department of Chemistry, Polydisciplinary Faculty of Nador,
University Mohammed Premier, Oujda, Morocco
3
LPGE, Faculty of Sciences, University Mohammed Premier,
Oujda, Morocco
Finally, there is a considerable efort to develop a new
efficient and inexpensive method to synthesize chal-
cones [13–17]; several synthetic methods are available
in the literature. The most used is the Claisen–Schmidt
4
Laboratoire des Multimatériaux et Interfaces (LMI),
Université Claude Bernard Lyon 1, Villeurbanne, France
5
Institute of Nursing Professions and Health Techniques
of Fez, 30000 Fez, Morocco
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
S
N
S
N
S
N
HO
N
N
N
O
H
N
2b
2a
1
NEt2.HCl
O
S
N
S
N
S
N
N
N
N
R'
2c
O
3
R
4-7
O
Scheme 1 Structures of some biologically active (1–2) and synthesized (3–7) imidazo[2,1-b]thiazole derivatives
condensation, which is the oldest, simplest and most fre-
quently used reaction for chalcone synthesis. This pro-
cess consists in condensing equimolar methyl aryl ketone
amounts with an aryl aldehyde in an alcoholic medium and
in the presence of a base [13].
Amoxicillin for antifungal activity, and DMSO was used
as negative control.
To study the binding orientation to their protein targets,
some compounds were docked in order to help in the predic-
tion of the afnity/activity of the molecule.
As part of our program focusing on the discovery of
novel biologically active compounds and in light of the
above considerations, the extension of our previous work
on the search for new biologically powerful molecules has
been reported here [18]; in our search for novel biologi-
cally potent molecules, the synthesis and characterization
of new compounds possessed an imidazo[2,1-b]thiazole
scafold and assessed their antimicrobial activities against
three pathogenic bacteria (Pseudomonas aeruginosa,
Escherichia coli and Staphylococcus aureus) and one
pathogenic fungus (Fusarium oxysporum). Ciprofoxacin
was used as positive control for antibacterial activity and
Results and discussion
Spectroscopic characterization
The synthetic strategies adopted for constructing the target
molecules are illustrated in Scheme 2.
The synthetic method for the preparation of chalcone
analogues employing Claisen–Schmidt condensation of the
imidazo[2,1-b]thiazole carbaldehyde 3 and diferent methyl
ketones was used. This condensation is the most widely
Scheme 2 Route synthesis of the ligands (3–7)
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Journal of the Iranian Chemical Society
used method and is appreciated because of its relatively easy
implementation, availability and acceptable yields of end
products. This method has been previously reported [19].
The imidazo[2,1-b]thiazole carbaldehyde 3 was prepared by
the following literature procedures [5]. The carbaldehyde 3
was generated using Vilsmeier–Haack [20] reaction from
imidazo[2,1-b]thiazole 2, DMF and POCl3. Imidazo[2,1-
b]thiazole 2 was obtained by cyclocondensation between
2-aminothiazole and an α-halogenated carbonyl compound,
and this process was described by Hand and Paudler [21].
As shown in Scheme 2, a series of chalcone derivatives
were prepared by the condensation of aromatic aldehyde 3
and diferent methyl ketones in methanol [22, 23]. As soon
as the potassium hydroxide was added to the well-stirred
mixture of aldehyde 3 and methyl ketones, desired unsatu-
rated ketones (trans-alkene, E-form) were formed immedi-
difraction analysis. It crystallizes in the orthorhombic space
group Pbca.
A representative crystal structure is presented in Fig. 1.
The crystal data and structural refnement of 3 are shown
in Table 1. The imidazo[2,1-b]thiazole fragment is almost
planar [RMS deviation = 0.003 Å], and the phenyl ring
makes dihedral angle of [33.9(2)]° with this mean moiety.
The crystal packing is stabilized by intermolecular C—H···N
hydrogen bonds. As depicted in Table 2, most bond lengths
were within the normal ranges: the C–C single bond is in
the range of 1.339(2)–1.468(2) Å and the N–C bond lengths
registered around 1.326(1) to 1.390(2) Å (see Table 1).
Figure 2 shows the stacking of the crystal structure of 3.
The layers develop in parallel planes along the c-axis, and
the structure is stabilized by strong intermolecular bonds
[C–H…N] and other van der Waals interactions forming a
two-dimensional network of molecules connected to each
other, thereby reinforcing the cohesion of the structure. Fur-
ther information is available in supplementary data.
1
ately as judged by H NMR spectroscopy. Yields ranged
between 74 and 82% without optimization.
To confrm the chemical structures of all the synthesized
compounds, spectroscopic techniques were used. Indeed, 1H
NMR spectra of these compounds exhibit the expected char-
acteristic protons. In the 1H NMR spectra of compounds 4, 5
and 7, a singlet from 2.3 ppm to 4.3 ppm was found and was
attributed to methyl protons (three methyl) and the multiplet
between 6.7 and 8.4 ppm was ascribed to aromatic protons.
Doublets corresponding to alkene protons were detected in
the range of 6.80–8.20 ppm with aromatic protons. The reso-
nance of diferent carbons at 110–160 ppm was attributed
to aromatic carbons. The conjugated ketone’s carbon was
Antibacterial activity
The antibacterial activity related to action of the fve com-
ponents of the imidazothiazole derivatives 3, 4, 5, 6 and
7 tested showed diferent inhibitory activities. According
to the results shown in Table 2, the compound 3 showed
a strong inhibitory efect against Pseudomonas aeruginosa
and E. coli with a MIC≤0.2 mg/ml and sensitivity against
S. aureus (MIC≤0.5 mg/ml). This may be due to the pres-
ence of a carbonyl oxygen atom which can form a hydrogen
bond with the active site of the enzymes of the bacterium
(Table 2).
shielded and was assigned to the signal at 177 ppm in 13
C
NMR spectra of 6 and 7. The variation of the substituent of
the same carbon induced the up-feld shift in the frequencies
to 186 ppm for 4 and 200 ppm for 5.
The chemical structures of the synthesized imidazo[2,1-
b]thiazole derivatives were confrmed by mass spectrometry.
Further information about the isolation and full characteriza-
tion of these compounds is provided in the “Experimental”
section.
Table 1 Hydrogen-bond geometry (Å, °)
D—H···A
D—H
H···A
D···A
D—H···A
C9—H91···N3
0.987
2.544
3.4416 (19)
151.13
Compound 3 has been successfully crystallized, and
its structure has been determined by single-crystal X-ray
Symmetry code: x+1/2, y and −z+1/2
Fig. 1 a The molecular structure of 3. b Dihedral angle of imidazothiazole ring with the phenyl ring in the crystal of 3
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Journal of the Iranian Chemical Society
Table 2 The diameter of inhibition and the MIC of fve imidazothiazole compounds tested on three bacterial strains
Compound
Conc. of com-
pound (μg/ml)
Bacterium
E. coli
P. aeruginosa
S. aureus
ID (mm)
MIC (μg/ml)
200
ID (mm)
MIC (μg/ml)
200
ID (mm)
MIC (μg/ml)
500
3
6
1000
500
200
50
1000
500
200
50
15
12
9
16
13
10
6
12
8
6
6
6
–
–
–
–
–
13
10
6
6
23
500
25
–
–
–
–
–
Ciprofoxacin
Amoxicillin
Negative control
DMSO
22
–
–
20
–
–
22
–
–
19
–
–
–
–
–
–
ID inhibition diameter, MIC minimal inhibitory concentration, – no activity
Fig. 2 The crystal packing of 3 viewed along the b–c axis
Compound 6 reveals activity against P. aeruginosa with
an MIC≤0.5 mg/ml. This activity may be due to the pres-
ence of furan oxygen, which can form a hydrogen bond with
the amino acids. While the other ligands have no activity on
the tested bacterial strains, this is probably due to the steric
hindrance of these compounds which can prevent interac-
tions with the active sites of the enzymes. To confrm these
results, molecular docking was realized.
is completely inhibited by 3, 4, 5, 6 and 7 with IC50 not
exceeding 0.07 mg/ml.
Molecular docking studies
The MOE program was used in this study because of the
presence of various highly developed utilities and functions
that allow us to give more realistic results, especially that
concerning the calculation of protein–ligand binding free
energy [score energy (S)]. This energy is calculated using
a formalism taken into account the explicit hydrogens or
electrostatic efects in computation [24, 25].
Antifungal activity
The antifungal test of the fve imidazothiazole derivatives
experienced at fve diferent doses acted diferently on the
mycelia F. oxysporum. From Table 3, all the molecules
showed very interesting results. Indeed, the mycelial growth
Thymidylate kinase (TMPK) is a crucial chemothera-
peutic target due to its direct involvement in the synthe-
sis of thymidine triphosphate, an essential component
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Journal of the Iranian Chemical Society
Table 3 Growth inhibition rates
(%) of the Fusarium oxysporum
and IC50 values (mg/mL) for
each product tested
Compound
Concentration (mg/mL)
IC50(mg/ml)
0.01
0.05
0.2
1
5
3
20
15
30
16
20
0
50
47
65
47
48
0
81
78
95
80
80
0
97
93
100
100
100
100
100
0
0.05
0.07
0.02
0.06
0.05
–
4
5
100
97
95
0
6
7
Negative control
DMSO
0
0
0
0
0
–
Table 4 Docking results of the tested compounds
Gln105, Thr101 and Arg74 which are in total accordance
with the experiment results.
Compound S (kcal/mol) RMSD (Å) Amino acids
The results of the molecular docking studies (Table 4)
demonstrated that the two tested ligands interact with
acid residues of Thymidylate kinase enzyme. Compound
3 showed a hydrogen bond formed between the oxygen of
the carbonyl moiety and Gln105 with a distance equal to
1.86 Å. Also, it revealed a weak interaction between the
sulfur atom and the amino acid Glu39 with a distance equal
to 3.19 Å (Fig. 4). However, there are no interactions to the
two residues Thr101 and Arg74. A strong docking score of
about −6.59 kcal/mol was calculated, and it is comparable
to the one obtained for the co-crystallized compound 0DF
(S=−7.81 kcal/mol). From these results, we can postulate
that 3 has a strong binding afnity to the active site of the
receptor and also can exhibit a good and similar efect as
0DF.
0DF
3
6
−7.81
−6.59
−4.02
0.242
0.887
0.949
Gln105, Thr101 and Arg74
Gln105 and Glu39
Arg50 and Arg96
implicated in DNA replication, so inhibiting the func-
tion of this enzyme blocks DNA synthesis in replicating
organisms [26, 27]. In fact, this enzyme catalyzes the
conversion of thymidine 5′-monophosphate (dTMP) to
thymidine 5′-diphosphate (dTDP) in the presence of ATP
(adenosine triphosphate) and magnesium. Some known
proposed inhibition mechanisms of TMPK enzymes are
based essentially on the fact that the inhibitor afects the
afnity of the enzyme for ATP by binding to the same site
as ATP, not identical wholly or in part to the substrate-
binding site for ATP, which makes the rate of formation
of products slower, and thus results in the decrease in the
catalytic activity of the enzyme. Actually, all the reported
TMK inhibitors are thymidine analogues due to its cell
permeability. Therefore, small-molecule TMK inhibitors,
or nonsubstrate analogues, are necessary to develop anti-
bacterial therapeutics. Herein, we report nonthymidine
inhibitors targeting TMK enzyme in order to explain their
antibacterial efect.
The binding mode of compound 6 shows that the car-
bonyl group makes a hydrogen bond with Arg96 (dis-
tance=2.04 Å), while the oxygen in the furan ring forms a
hydrogen bond of 1.89 Å with the amino acid Arg50 (Fig. 5).
Unfortunately, compound 6 formed no interactions similar
to those displayed with 0DF. These observations may sup-
port the postulation that this compound may have a diferent
efect to that observed by 0DF.
Experimental
Based on the in vitro antibacterial screening, the two
compounds 3 and 6 were docked into the active site of
Thymidylate kinase protein to rationalize the experimen-
tal results and to evaluate its binding mode into the target
enzyme. The docking score energy (S), RMSD values and
interactions with amino acid residues of the studied com-
pounds are summarized in Table 4.
Materials
The employed reagents were acquired from Aldrich and
used without further purifcation. All the solvents were
dried by adapted agents and distilled accordingly. The
melting points were determined with a Tottoli apparatus.
The docking reliability was validated by re-docking co-
crystallized ligand (0DF) into the binding site of P. aerugi-
nosa Thymidylate kinase. A score of − 7.81 kcal/mol was
calculated for 0DF, and the predicted pose was similar to
the experimental pose in the original crystal structure with a
RMSD=0.242 Å (Fig. 3). Predicted pose of the ligand 0DF
showed H-bonding interactions with amino acid residues
1
The H and 13C NMR were taken in CDCl3 or DMSOd6
using NMR Bruker Avance DPX 500 MHz spectrometer
500 MHz for 1H and 126 MHz for 13C. Chemical shifts δ
are expressed in unit parts per million (ppm) and are still
zeroed at tetramethyl silane (TMS) peak. Mass spectra
have been performed on PerkinElmer SCIEX API 3000
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Journal of the Iranian Chemical Society
Fig. 3 3D (a) and 2D (b) superposition of predicted (green) and experimental (red) poses of the ligand 0DF into the binding site of P. aerugi-
nosa Thymidylate kinase
Fig. 4 3D and 2D interactions of 3 into the binding site of P. aeruginosa Thymidylate kinase
model. Thin layer chromatography (TLC) was used for
monitoring reactions, using Merck silica gel 60 F254 pre-
coated aluminum plates. UV light and I2 were used for
visualization. The chromatographic separations were car-
ried out on silica gel columns (Merck, 60–120 mesh).
Synthesis
6-phenylimidazo[2,1-b]thiazole-5-carbaldehyde 3 This
product is prepared by the following literature procedures
[5].
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Journal of the Iranian Chemical Society
Fig. 5 3D and 2D interactions of compound 6 into the binding site of P. aeruginosa Thymidylate kinase
4H), 7.53–7.45 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.85 (t,
General procedure for the preparation of chalcone
of imidazothiazole
3H, CH3); 13C NMR (126 MHz, DMSO) δ 186.83, 163.09,
153.50, 152.52, 133.49, 130.91, 130.48, 128.79, 128.76,
128.66, 128.55, 121.71, 120.21, 116.01, 115.19, 113.88,
55.54; LC–MS: m/z=361 (M+1).
To carbaldehyde 3 (0.5 mmol) in 15 ml of ethanol was added
1 ml of 10% aqueous KOH solution, and the mixture was
stirred for 15–20 min at 60 °C. To this mass p-acetophenone
(0.5 mmol) were added, and the mixture was stirred. The
reaction was monitored by TLC. After 6–8 h, the mixture
was poured in ice cold water and acetic acid was added for
neutralization. Finally, the fltration gives the crude imida-
zothiazoles, which were purifed by column chromatography
on silica gel (ethyl acetate–hexane, 2:8) afording pure imi-
dazothiazoles 4–7.
(E)‑1‑mesityl‑3‑(6‑phenylimidazo[2,1‑b]thiazol‑5‑yl)
prop‑2‑en‑1‑one 5
Yellow solid from acetomesitylene (75% Yield); Mp:
200–201 °C; 1H NMR (500 MHz, Chloroform-d) δ (ppm):
7.87 (d, J = 4.5 Hz, 1H), 7.62–7.52 (m, 3H), 7.47–7.35
(m, 3H), 6.92 (s, 2H), 6.71 (d, J = 16.4 Hz, 1H), 2.30 (d,
J=34.2 Hz, 10H); 13C NMR (126 MHz, Chloroform-d) δ
200.58, 154.39, 153.78, 138.46, 136.91, 133.91, 133.23,
132.86, 128.76, 128.66, 128.43, 122.32, 119.65, 114.28,
21.15, 19.38; LC–MS: m/z=373(M+1).
S
N
1'
N
2'
2
1
3
(E)‑1‑(furan‑2‑yl)‑3‑(6‑phenylimidazo[2,1‑b]thiazol‑5‑yl)
prop‑2‑en‑1‑one 6
R
O
Yellow solid from 2-acetylfuran (71% Yield); Mp:
170–171 °C; 1H NMR (500 MHz, Chloroform-d) δ (ppm):
8.15 (d, J=15.8 Hz, 1H), 7.94 (d, J=4.5 Hz, 1H), 7.79–7.73
(m, 2H), 7.66 (dd, J=1.7, 0.8 Hz, 1H), 7.57–7.49 (m, 2H),
7.50–7.43 (m, 1H), 7.34–7.29 (m, 1H), 7.26 (s, 1H), 7.10
(E)‑1‑(4‑methoxyphenyl)‑3‑(6‑phenylimidazo[2,1‑b]
thiazol‑5‑yl)prop‑2‑en‑1‑one 4
(d, J=4.5 Hz, 1H), 6.62 (dd, J=3.6, J=1.7 Hz, 1H); 13
C
Yellow solid from 4-methoxyacetophenone (74% Yield)
1
NMR (126 MHz, Chloroform-d) δ 177.64, 154.03, 153.95,
146.08, 133.52, 130.02, 129.10, 128.84, 120.61, 119.70,
116.87, 115.55, 114.13, 112.73; LC–MS: m/z=321(M+1).
Mp: 195–196 °C; H NMR (500 MHz, DMSO-d6) δ 8.72
(d, J=4.6 Hz, 1H), 8.23–8.15 (m, 2H), 7.91 (d, J=15.6 Hz,
1H), 7.76–7.66 (m, 2H), 7.59 (m, J = 27.2, 9.2, 6.2 Hz,
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Journal of the Iranian Chemical Society
(E)‑1‑(5‑methylfuran‑2‑yl)‑3‑(6‑phenylimidazo[2,1‑b]
thiazol‑5‑yl)prop‑2‑en‑1‑one 7
was determined by the linear regression equation between
the natural logarithm of the concentrations and the growth
inhibition percentages [28].
Yellow solid from 2-acetyl-5-methylfuran (82% Yield); Mp:
215–216 °C; 1H NMR (500 MHz, Chloroform-d) δ (ppm):
8.45 (d, J=7.5 Hz, 1H), 7.88 (d, J=15.2 Hz, 1H), 7.71 (d,
J = 7.5 Hz, 1H), 7.60 (m, J = 5.7, 2.4, 2.0 Hz, 2H), 7.42
(dp, J=3.2, 2.0 Hz, 3H), 7.24 (d, J=7.3 Hz, 1H), 6.69 (d,
X‑ray data collection and structure determination
X-ray diffraction pattern of 3 was collected by using
Oxford Difraction Gemini difractometer [29]. The exper-
iments were performed at 293 K with Mo Kα radiation
(λ = 0.71069 Å). Cell refnement was carried out using
Chrysalis [30]; program(s) used to solve structure: SIR97
[31]; program(s) used to refne structure: CRYSTALS
[32]; molecular graphics: CAMERON [33]; and software
used to prepare material for publication: CRYSTALS [32].
Refnement of F2 against all refections. The weighted
R-factor wR and goodness of ft S are based on F2, and con-
ventional R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >σ(F2) is used
only for calculating R-factors(gt), etc., and is not relevant
to the choice of refections for refnement. R-factors based
on F2 are statistically about twice as large as those based
on F, and R-factors based on all data will be even larger.
Table 5 summarizes the pertinent crystallographic data
and refnement details of 3.
J=15.0 Hz, 1H), 6.29 (d, J=7.5 Hz, 1H), 2.39 (s, 3H); 13
C
NMR (126 MHz, Chloroform-d) δ 177.03, 157.64, 153.61,
153.48, 152.73, 133.65, 129.50, 129.09, 128.82, 128.76,
120.63, 119.55, 118.89, 116.23, 113.99, 109.47, 14.27.;
LC–MS: m/z=335 (M+1).
Antibacterial test
The antibacterial activity of fve imidazothiazole derivatives
3, 4, 5, 6 and 7 was evaluated by the difusion method in agar
medium on strains of P. aeruginosa, E. coli and S. aureus
using the concentrations C1: 1000 μg/ml; C2: 500 μg/ml; C3:
200 μg/ml and C4: 50 μg/ml. The used test was that recom-
mended by the NCCLS (National Committee for Clinical
Laboratory Standards) and described by the AFNOR 2004:
NF-U47-107.
From young colonies of 18–24 h, a bacterial suspension
is carried out in sterile physiological water for each strain.
The turbidity of this suspension is adjusted to 0.5 McFar-
land. This inoculum is seeded by fooding on Petri dishes
containing Mueller–Hinton agar.
Table 5 Crystal data and structural refnement of compound 3
The Whatman paper disks (6 mm) are placed and soaked
in the diferent tested compounds and then gently deposited
on the surface of the agar. The same is true for ciprofoxa-
cin disks against P. aeruginosa, Amoxicillin against E. coli
and S. aureus. The Petri dishes are frst left for 1 h at room
temperature for predifusion of the substances, before being
incubated at 37 °C in an oven for 24 h. Antibacterial activity
is determined by measuring the diameter of the inhibition
zone around each disk to determine the lowest concentra-
tion of tested antimicrobial that inhibits the growth of the
bacterium-tested MIC [28].
Chemical formula
Mr
C12H8N2OS
228.27
T=293 K
Orthorhombic, P b c a
Temperature (K)
Crystal system, space group
a, b, c (Å)
Β (°), λ (Å)
V (Å3)
12.6730(4), 7.2844(3), 22.7774(9)
97.449(12), 0.71069
2102.70(14)
8
1.442
0.284
Z
Dx (g/cm3)
µ
F(000)
944
Crystal size (mm3)
Radiation
θ range (°)
Tmin/Tmax
0.243×0.400×0.505
Mo Kα (λ=0.71069 Å)
3.215–29.418
0.900/0.930
0.023
0.0439
0.0365
Antifungal test
The antifungal action of fve imidazothiazole derivatives 3,
4, 5, 6 and 7 is carried out on a F. oxysporum using the con-
centrations: C1: 5 mg/ml; C2: 1 mg/ml; C3: 0.2 mg/ml; C4:
0.05 mg/ml and C5: 0.01 mg/ml.
Rint
wR (F2)
R[F2 >2σ(F2)]
S (F2)
Each compound was added to the potato dextrose agar
(PDA) at diferent concentrations before culturing the fun-
gus. Fungal cultures were incubated at 28 °C for 5 days.
The inhibition percentage of each compound was calcu-
lated by the ratio of the mycelium diameter observed when
using it over that observed in the negative control. IC50
1.063
12028/2589/2200
Measured refections/independ-
ent refections/refections with
I>2σ(I)
∆ρmax/∆ρmin (Å−3
)
0.19/−0.24
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Journal of the Iranian Chemical Society
4. G.D. Kapche, C.D. Fozing, J.H. Donfack, G.W. Fotso, D. Ama-
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Molecular docking simulation
The ligand–protein docking study was performed using
MOE (2014.09 software) [34]. The crystal structure of
the Thymidylate kinase from P. aeruginosa bound with
1-methyl-6-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyri-
din-2-one (0DF) (PDB code: 3UWK) was retrieved from
Protein Data Bank (http://www.rcsb.org/). Hydrogens
were added, partial charges were calculated, and water
molecules and cofactors were removed. Docking study was
carried out following the standard protocol implemented
in MOE (2014.09). Structure of the selected compounds
was built in ACD/ChemSketch [35], and geometry was
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synthesized with good yields by simple condensation
between 2-aminothiazole and a diferently substituted
α-halogenated carbonyl compound. All new compounds
were characterized by MS, 1H and 13C NMR. The in vitro
antimicrobial activities of these imidazothiazole deriva-
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uginosa, E. coli and S. aureus) and one fungal strain (F.
oxysporum). The preliminary results of these compounds
against the studied microorganisms showed moderate-to-
good antibacterial and antifungal activities. Indeed, 3 and
6 exhibited promising antimicrobial activity. Regarding
the antifungal activity, all the molecules showed very
interesting results versus F. oxysporum. These results were
confrmed by a theoretical molecular docking study where
it revealed that the two compounds 3 and 6 can make
hydrogen bonds with many amino acid residues of the
active site of P. aeruginosa Thymidylate kinase enzyme.
The results of this study can support the postulation that
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