Synthesis of some new 2-(3-pyridyl)-4,5-disubstituted thiazoles as potent antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2012.12.050

As a part of ongoing studies in developing new potent antimicrobial agents, a series of novel 2-(3-pyridyl)-4,5-disubstituted thiazoles was efficiently synthesized and characterized by spectral and elemental analyses. The newly synthesized compounds were evaluated for their in vitro antimicrobial activity against ten bacterial and five fungal human pathogenic strains using the disc diffusion assay. Among the synthesized compounds, 5-acetyl-4-methyl-2-(3- pyridyl)thiazole (5) exhibited twofold antibacterial activity of ampicillin in inhibiting the growth of Staphylococcus epidermidis (MIC 0.24 μg/mL) and also showed equipotent antifungal activity with amphotricin B against Geotricum candidum (MIC 0.48 μg/mL). From structure-activity relationship (SAR) point of view, increasing the size of the substitutions either at position 4 or 5 on the thiazole nucleus decreased the antimicrobial activity.

Full text of DOI:10.1016/j.ejmech.2012.12.050

European Journal of Medicinal Chemistry 62 (2013) 270e279
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of some new 2-(3-pyridyl)-4,5-disubstituted
thiazoles as potent antimicrobial agents
,
b
,
c
,
,e
Samir Bondock a , Tamer Naser d, Yousry A. Ammar b
*
a Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt
b Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Egypt
d Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Khalid University, 61441 Abha, Saudi Arabia
e Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of ongoing studies in developing new potent antimicrobial agents, a series of novel 2-(3-
pyridyl)-4,5-disubstituted thiazoles was efficiently synthesized and characterized by spectral and ele-
mental analyses. The newly synthesized compounds were evaluated for their in vitro antimicrobial ac-
tivity against ten bacterial and five fungal human pathogenic strains using the disc diffusion assay.
Among the synthesized compounds, 5-acetyl-4-methyl-2-(3-pyridyl)thiazole (5) exhibited twofold
Received 15 November 2012
Received in revised form
26 December 2012
Accepted 27 December 2012
Available online 5 January 2013
antibacterial activity of ampicillin in inhibiting the growth of Staphylococcus epidermidis (MIC 0.24
mL) and also showed equipotent antifungal activity with amphotricin B against Geotricum candidum (MIC
0.48 g/mL). From structureeactivity relationship (SAR) point of view, increasing the size of the sub-
mg/
Keywords:
Thiazole
Pyridine
Pyrazoline
Chalcone
m
stitutions either at position 4 or 5 on the thiazole nucleus decreased the antimicrobial activity.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Antimicrobial activity
1. Introduction
integral part of all the available penicillins, which have revolu-
tionized the therapy of bacterial diseases [6]. Thiazoles have
The treatment of infectious diseases remains an important issue
because of a combination of factors including emerging newer in-
fectious diseases and increasing number of multi-drug resistant
microbial pathogens. This problem is particularly pronounced for
the Gram-positive bacteria [1e4]. The therapeutic problem is an
important part of hospitalized patients, immunosuppressed pa-
tients with AIDS and those undergoing anticancer therapy or organ
transplants. Despite a large number of antibiotics and chemother-
apeutics available for medical use, the emerging resistance to old
and new antibiotics has created a substantial need for new classes
of antimicrobial agents. A potential approach to overcome the
problem of antibiotic resistance is to design innovative agents with
different modes of action so that no cross resistance with present
drugs can occur [5].
attracted continuing interest because of their varied biological
activities [7], which have found applications in the treatment of
allergies [8], hypertension [9], inflammation [10], schizophrenia
[11], microbial infections [12,13], HIV infections [14], hypnotics [15]
and for the treatment of pain [16]. They have been also used as
fibrinogen receptor antagonists with antithrombotic activity [17]
and as new inhibitors of bacterial DNA gyrase B [18].
On the other hand, chalcone, a biosynthetic product of the shi-
kimate pathway, is a separate class of compounds, those have a wide
range of biological properties. Chalcones are useful synthons in the
synthesis of a large number of bioactive molecules such as pyrazo-
lines that are well known nitrogen containing heterocyclic com-
pounds. Considerable interest has been focused on the pyrazoline
structure, which possesses a broad spectrum of biological activities
such as antiamoebic [19,20], antimicrobial [21], monoamine oxidase
inhibitors [22], antimycobacterial [23,24], antidepressant [25,26],
anticonvulsant [27] and anti-inflammatory [28,29].
Thiazoles are a familiar group of heterocyclic compounds pos-
sessing a wide variety of biological activities, and their usefulness
as medicines are well established. Thiazole nucleus is also an
Moreover, the pyridine nucleus is prevalent in numerous natural
products and is extremely important in the chemistry of biological
systems. Pyridine derivatives have been used as bactericides [30],
fungicides [31], and anticancer agents [32e35].
* Corresponding author. Department of Chemistry, Faculty of Science, Mansoura
University, ET-35516 Mansoura, Egypt.
E-mail address: Bondock@mans.edu.eg (S. Bondock).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.12.050

S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
271
In view of the above-mentioned findings, and as a continuation
of our effort to identify new candidates that may be value in
designing new, potent, selective, and less toxic antimicrobial agents
[36e39], we report herein the synthesis and antimicrobial evalu-
ation of some novel structure hybrids incorporating the pyridine,
thiazole and pyrazole ring systems. This combination was sug-
gested to investigate the influence of such hybridization and
structure variation on the anticipated biological activities, hoping
to add some synergistic biological significance to the target mole-
cules. The target compounds were rationalized so as to comprise
some pharmacophores that are believed to be responsible for the
biological activity of some relevant chemotherapeutic agents such
as the acetyl and chalcone functionalities. The substitution pattern
of the thiazole and pyrazole rings was carefully selected in order to
confer different electronic environment to the molecules.
methyl and acetyl protons. The 13C NMR spectrum displayed eleven
carbon signals, the most important signals appeared at 17.9, 30.3,
d
190.7 ppm characteristic for two methyl and carbonyl carbons,
respectively. The mass spectrum revealed a molecular ion peak at
m/z ¼ 218 corresponding to a molecular formula C11H10N2OS.
The presence of the acetyl group in the thiazole 5 makes
it versatile precursor for the synthesis of chalcones and
pyrazoline derivatives. Thus, the ClaiseneSchmidt condensation of
5-acetylthiazole 5 with aromatic aldehydes in ethanolic sodium
hydroxide furnished the chalcone derivatives 6aee. The structure
of the latter products were confirmed by IR spectra which showed
the characteristic band for conjugated C]O at 1652e1660 cmꢀ1
and their 1H NMR spectra displayed a pair of doublets at
d 7.35e
7.49 and 7.71e7.75 ppm, with coupling constant value (J ¼ 15.0e
15.5 Hz), due to the trans-olefinic protons. Cyclocondensation of
chalcones 6aee with hydrazine hydrate in boiling ethanol fur-
nished the respective pyrazolines 7aee (Scheme 2). The structures
of the pyrazolines were established by IR spectra which showed
disappearance of C]O band of chalcones. A strong band appeared
at 1590e1605 cmꢀ1 assigned to C]N of pyrazoline ring. Pyrazo-
lines 7aee showed an additional sharp band in the region 3200e
3235 cmꢀ1 due to their NH stretching. Their 1H NMR spectra
revealed the signals of CH2 protons of the pyrazoline ring in the
region 2.79e2.98 and 3.25e3.62 ppm as a pair of doublets. The CH
proton appeared as double of doublets at 4.90e4.98 ppm. The 13C
NMR spectrum of compound 7a, as a representative example, dis-
played, besides the expected methyl and aromatic signals, three
2. Results and discussion
2.1. Chemistry
The synthetic strategies adopted for the synthesis of the target
compounds are depicted in Schemes 1 and 2. In Scheme 1, the
Hantzsch reaction of thionicotinamide (1) with
a-haloketones,
namely p-chloroacetylacetanilide [40], 3-bromoacetylcoumarin
[41], chloroacetone and 3-chloroacetylacetone in refluxing etha-
nol containing a catalytic amount of triethylamine afforded, in each
case, a single product, that was identified as 2-(3-pyridyl)thiazole
derivatives 2e5. It has been found that elemental analysis and
spectral data were in consistent with the proposed 2-(3-pyridyl)
thiazole structures. The IR spectrum of 1-(4-methyl-2-(3-pyridyl)
thiazol-5-yl)ethanone (5), as a representative example, showed
a strong absorption band at 1695 cmꢀ1 that is due to a carbonyl
group. Its 1H NMR spectrum showed besides the expected aromatic
characteristic signals at
d 42.4, 64.3 and 160.2 ppm due to the
carbons of CH2, CH and C]N of pyrazoline ring, respectively.
2.2. Antimicrobial evaluation
The antimicrobial screening and minimal inhibitory concentra-
tions of the tested compounds were carried out at the Regional
signals, two new singlets at
d
2.65 and 2.75 ppm assigned to the
S
N
AcHN
COCH2Cl
N
EtOH/TEA
2
AcHN
O
O
Br
S
N
N
O
EtOH/TEA
O
O
S
3
N
NH2
O
1
Cl
N
S
Me
EtOH/TEA
N
Me
O
4
O
O
Me
Me
Me
N
S
Cl
N
EtOH/TEA
Me
5
Scheme 1. Synthesis of 2-(3-pyridyl)thiazoles 2e5.

272
S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
O
O
N
Ar
S
N
S
Me
ArCHO
EtOH/NaOH
N
N
Me
Me
6a-e
5
6-7 Ar
H
N
a
C6H5-
N
b
c
d
e
4-CH3O-C6H4-
4-Cl-C6H4-
2-NO2-C6H4-
2,4-F2C6H3-
Ar
NH2NH2.H2O
EtOH
N
S
N
Me
7a-e
Scheme 2. Synthesis of chalcones 6aee and pyrazolines 7aee.
Center for Mycology and Biotechnology, Al-Azhar University, Cairo,
Egypt. Thirteen of the newly synthesized target compounds were
evaluated for their in vitro antimicrobial activities against the hu-
man pathogens Staphylococcus aureus (RCMB 010027), Staphylo-
coccus epidermidis (RCMB 010024), Streptococcus pyogenes (RCMB
010015), Bacillis subtilis (RCMB 010063) and Enterococcus faecalis
(RCMB 010068) as examples of Gram-positive bacteria and Neis-
seria gonorrhoeae (RCMB 010076), Proteous vulgaris (RCMB 010085),
Klebsiella pneumonia (RCMB 010093), Shigella flexneri (RCMB
0100542) and Pseudomonas aeruginosa (RCMB 010043) as examples
of Gram-negative bacteria. They were also evaluated for their po-
tential antifungal activities against the following fungal strains;
Aspergillus fumigates (RCMB 02564), Aspergillus clavatus (RCMB
02593), Candida albicans (RCMB 05035), Geotricum candidum
(RCMB 05096), and Penicillium marneffei (RCMB 01267).
2.2.1. Antibacterial activity
Preliminary antibacterial screening was carried out for the
substituted 2-(3-pyridyl)thiazoles 2e5. Among this series, com-
pounds 3e5 showed good inhibitory activity against all the
screened Gram-positive bacteria (Fig. 1). Compounds 4 and 5
showed better results when compared with ampicillin as revealed
from their MIC values (0.97e31.25 mg/mL) and (0.06e7.81 mg/mL),
respectively, with superior activity for compound 5 (Table 1). The
5-acetylthiazole 5 showed twofold potency of ampicillin in inhib-
iting the growth of S. epidermidis (MIC 0.24
potency of ampicillin against S. aureus and E. faecalis with MIC
values (0.24 g/mL) and (7.81 g/mL), respectively. 4-Methyl-2-(3-
pyridyl)thiazole 4 displayed 50% less activity compared to ampi-
cillin against S. epidermidis (MIC 0.97 g/mL). The results depicted
mg/mL) and 25% of the
m
m
m
in Fig. 1 revealed that the coumarinylthiazole 3 showed moderate
Agar-diffusion method was used for the determination of the
preliminary screening of antibacterial and antifungal activities.
Ampicillin, gentamycin and amphotricin B were used as reference
drugs. The results were recorded for each tested compound as the
average diameter of inhibition zones (IZ) of bacterial or fungal
growth around the discs in mm. The minimal inhibitory concen-
trations (MICs) for compounds that showed significant growth in-
hibition zones (>10 mm) were determined using twofold serial
dilution method [42]. The inhibition zone diameters, attributed to
the tested original concentration (5 mg/mL) as a preliminary test,
to weak activity against the growth of the different Gram-positive
bacteria (MIC 3.9e62.5
mg/mL), and its best result was observed
against S. epidermidis (MIC 3.9
mg/mL). On the other hand, com-
pound 2 showed narrow spectrum of activity in inhibiting the
growth of Gram-positive bacteria as it was inactive against
S. pyogenes and E. faecalis and showed 25% the activity of ampicillin
against S. epidermidis (MIC 1.95 mg/mL).
By investigating the biological activity of the substituted 2-(3-
pyridyl)thiazoles 2e5 as anti-Gram negative bacterial agents
(Fig. 2), it was observed that compounds 3e5 were only
active with broad spectrum activity against all the screened mi-
crobes. Unfortunately, compound 2 was completely inactive.
are shown in Figs. 1e6 and the MICs (
mg/mL) are shown in Tables 1
and 2.
Fig. 1. Preliminary antibacterial activity of thiazoles 2e5 against Gram-positive bacteria.

S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
273
Fig. 2. Preliminary antibacterial activity of thiazoles 2e5 against Gram-negative bacteria.
Interestingly, 5-acetylthiazole 5 was one-fold less active than
gentamycin against N. gonorrhoeae, P. vulgaris and K. pneumonia
Concerning the antibacterial activity of pyrazoline derivatives,
the results displayed that compounds 7aec and 7e were active
against all screened Gram-positive bacteria except S. pyogenes and
their potencies were weaker than that of their corresponding
chalcones 6aee (Fig. 3). Moreover, pyrazoline 7b showed narrow
spectrum of activity on contrast to its corresponding chalcone 6b.
Similarly, the effect of chalcones 6aee, pyrazolines 7aec and 7e
on Gram-negative bacteria was also tested. The results are illus-
trated in Fig. 4. Surprisingly, chalcones 6b and 6d were only showed
weak to moderate broad spectrum activity against all the screened
Gram-negative bacteria. Chalcones 6b and 6d recorded twofold
with MIC values (15.63
respectively, and showed weak effect in inhibiting the growth of
S. flexneri (MIC 3.9 g/mL). Thiazole 4 was 50% less active than
gentamycin against P. vulgaris (MIC 3.9 g/mL) and 75% less active
than gentamycin against the growth of P. aeruginosa (MIC 125 g/
mL). The coumarinylthiazole 3 was 50% less active than genta-
mycin against P. aeruginosa (MIC 62.5 g/mL) and 75% less active
than gentamycin against S. flexneri (MIC 1.95 g/mL); while its
effect against N. gonorrhoeae and P. vulgaris was much weaker
mg/mL), (3.9 mg/mL) and (0.48 mg/mL),
m
m
m
m
m
than gentamycin with MIC values (62.5
respectively.
m
g/mL) and (15.63
m
g/mL),
lower potency than gentamycin against P. vulgaris (MIC 7.81
mL); chalcone 6d also showed twofold lower potency than genta-
mycin in inhibiting the growth of K. pneumonia (MIC 0.97 g/mL)
and P. aeruginosa (MIC 125 g/mL). On the other hand, chalcone 6a
was active against P. vulgaris, K. pneumonia and S. flexneri; while
chalcones 6c and 6e were active against P. vulgaris and
K. pneumonia only and their potencies were weaker than chalcones
6b and 6d. Unexpectedly, among the pyrazolines 7aec and 7e, only
pyrazoline 7b was the active one as it showed activity against all the
screened Gram-negative bacteria except P. aeruginosa with weaker
potency than their corresponding chalcone 6b.
mg/
The above results revealed that the 5-aceylthiazole 5 showed
the best antibacterial activity. For that reason, compound 5 was
chemically transformed to the respective chalcone 6aee and pyr-
azoline 7aee derivatives hoping to get more potent antibacterial
agents. From the chalcone series 6aee, compounds 6b and 6d only
showed broad spectrum activity against all the screened Gram-
positive bacteria with weak to moderate potency (Fig. 3). In con-
trast to the activity of the precursor 5-acetylthiazole 5, chalcone 6d
showed 50% potency of ampicillin against S. epidermidis (MIC
m
m
0.97
m
g/mL); while chalcone 6b showed three fold weaker potency
The results of antibacterial screening revealed that most of the
tested thiazoles displayed variable inhibitory effects on the growth
of tested Gram-positive and Gram-negative bacterial strains. In
general, most of the studied thiazoles revealed better activity
against the Gram-positive rather than Gram-negative bacterial
against the same bacteria (MIC 3.9
mg/mL) (Table 1). The chalcones
6a and 6e were active against all the screened Gram-positive bac-
teria except S. pyogenes, while compound 6c was active against
S. aureus, S. epidermidis and B. subtilis only.
Fig. 3. Preliminary antibacterial activity of the chalcones 6aee and pyrazolines 7aec and 7e against Gram-positive bacteria.

274
S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
Fig. 4. Preliminary antibacterial activity of the chalcones 6aee and pyrazolines 7aec and 7e against Gram-negative bacteria.
strains. It was also observed that transformation of 5-acetylthiazole
5 to the respective chalcone and pyrazoline derivatives reduced the
antibacterial activity.
screened fungi (Fig. 5). Interestingly, the 5-acetylthiazole 5 was
equipotent to amphotricin B against G. candidum (MIC 0.48 g/mL)
and it showed 50% less potent effect than amphotricin B against
m
A. fumigates (MIC 1.95
P. marneffei (MIC 3.9
m
g/mL), A. clavatus (MIC 3.9
mg/mL) and
2.2.2. Antifungal activity
mg/mL). Moreover, 4-methyl-2-(3-pyridyl)
Regarding the activity of the substituted thiazoles 2e5 against
fungal strains, results in this study revealed that compounds 3e5
displayed broad spectrum antifungal activity against all the
thiazole 4 displayed, one-fold lower activity than that of ampho-
tricin B against P. marneffei (MIC 3.9 g/mL), twofold lower activity
against G. candidum (MIC 1.95 g/mL), and weak to moderate
m
m
Fig. 5. Preliminary antifungal activity of thiazoles 2e5.
Fig. 6. Preliminary antifungal activity of the chalcones 6aee and pyrazolines 7aec and 7e.

S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
275
Table 1
Antibacterial minimal inhibitory concentrations (MIC,
m
g/mL) of some new synthesized 2-(3-pyridyl)-4,5-disubstituted thiazoles.
Compounds
2
3
4
5
6a
6b
6c
6d
6e
7a
7b
7c
7e
AMPI
GEN
Gram-positive bacteria
S. aureus
3.9
1.95
eb
7.81
3.9
7.81
3.9
0.97
0.97
15.63
1.95
31.25
0.24
0.24
3.9
0.06
7.81
62.5
31.25
e
3.9
3.9
31.25
1.95
62.5
62.5
31.25
e
3.9
31.25
31.25
e
125
62.5
e
15.63
15.63
e
125
62.5
e
125
125
e
0.06
0.48
0.24
0.007
1.95
NTa
NT
NT
NT
NT
S. epidermidis
S. pyogenes
B. subtilis
0.97
62.5
0.97
62.5
0.97
e
31.25
500
31.25
e
15.63
250
62.5
125
15.63
250
62.5
125
62.5
125
E. faecalis
62.5
Gram-negative bacteria
N. gonorrhoeae
P. vulgaris
K. pneumonia
S. flexneri
e
e
e
e
e
62.5
15.63
7.81
1.95
62.5
62.5
3.9
1.95
3.9
15.63
3.9
0.48
3.9
e
125
7.81
3.9
7.81
250
e
125
7.81
0.97
7.81
125
e
e
e
e
e
e
500
31.25
62.5
62.5
e
e
e
e
e
e
e
e
e
e
e
NT
NT
NT
NT
NT
7.81
1.95
0.24
0.48
31.25
62.5
62.5
125
e
62.5
31.25
e
62.5
31.25
e
P. aeruginosa
125
500
e
e
AMPI, Ampicillin; GEN, Gentamycin.
a
NT, Not tested.
No activity.
b
ꢁ Replacement of the methyl group at position 4 of the thiazole
ring by hydrogen atom decreased the antimicrobial activity.
ꢁ Introduction of 3-coumarinyl moiety at position 4 of the thia-
zole ring resulted in biologically active compound 3 which was
quite less potent than thiazoles 4 and 5 and this may be due to
the huge size of the coumarin moiety. Its observed biological
activity could be attributed to the synergistic effect of both the
coumarin ring and 2-(3-pyridyl)thiazole nucleus as anti-
microbial moieties.
ꢁ Replacement of the small size acetyl group at position 5 of the
thiazole ring by bigger cinnamoyl group (AreCH]CHeCO)
resulted in decreasing the antimicrobial activity from one to
three folds.
potency against the rest of the tested fungi when compared with
the reference drug (MIC 7.81e31.25 g/mL). On the other hand,
compound 2 showed narrow spectrum of activity which is three to
four fold lesser than amphoticin B (MIC 7.81e15.63 g/mL).
Finally, the antifungal activity was tested for the chalcones 6ae
e and pyrazolines 7aec and 7e (Fig. 6). The chalcones 6aee
showed broad spectrum antifungal activity with lower potency
than 5-acetylthiazole 5. Chalcone 6b revealed twofold lower po-
m
m
tency than amphotricin B against P. marneffei (MIC 7.81
while chalcone 6d showed half potency against P. marneffei with
MIC values (7.81 g/mL) and (15.83 g/mL), respectively. Chal-
mg/mL);
m
m
cones 6a, 6c and 6e are equipotent and their potencies are weaker
than chalcones 6b and 6d. Among the pyrazolines, only 7b
showed broad spectrum antifungal activity with MIC values
ꢁ The presence of pyrazoloaryl moiety at position 5 of the thia-
zole nucleus resulted in the lowest antimicrobial activity
among all the tested compounds.
(31.25e250 mg/mL); while pyrazolines 7a, 7c and 7e were active
against all the screened fungi except C. albicans. In general, the
pyrazoline derivatives exhibited lower antifungal activity in
comparison to their corresponding chalcones and precursor
thiazole 5.
ꢁ Thetypeof the substitutions on the benzene ringof the chalcone
moiety is also important. It was noticed that the presence of
electron withdrawing groups such as chloride and fluoride at
the para and/or the ortho position of the benzene ring in chal-
cones 6c and 6e displayed no effect on the antimicrobial activity.
ꢁ The highest antimicrobial activities of the chalcone series were
observed in case of compounds 6b and 6d, those have the
electron donating methoxy group at the para position of the
benzene ring and electronwithdrawing nitrogroupon the ortho
position of the benzene ring, respectively. This indicates that the
type of the electronic effect of the benzene ring substitutions
have no effect; and it is suggested that the bigger size of the
substitutions on the benzene ring is responsible for the
observed high effect of these derivatives among their series as it
may cause the anchoring of these compounds to their target
receptor.
2.3. Structure activity relationship (SAR)
The results of the antimicrobial screening demonstrated the
following assumptions about the structural activity relationship
(SAR) (Fig. 7):
ꢁ It is interesting to point out that substituted 2-(3-pyridyl)
thiazole nucleus showed good antimicrobial activity.
ꢁ The highest antimicrobial activity observed when the sub-
stitutions at positions 4 and 5 of the thiazole nucleus are
smaller in size as the case of thiazoles 4 and 5.
ꢁ The presence of the electron withdrawing acetyl group at po-
sition 5 and small electron donating methyl group at position 4
of the thiazole 5 resulted in the highest antimicrobial activity
among all the compounds investigated in this study.
ꢁ The observed antimicrobial activity of compounds 6aee could
be attributed to the synergistic effect of both the 2-(3-pyridyl)
thiazole and chalcone moieties.
Table 2
Antifungal minimal inhibitory concentrations (MIC, mg/mL) of some new synthesized 2-(3-pyridyl)-4,5-disubstituted thiazoles.
Compounds
2
3
4
5
6a
6b
6c
6d
6e
7a
7b
7c
7e
AMPH
Fungi
A. fumigates
A. clavatus
C. albicans
G. candidum
P. marneffei
7.81
15.63
e
15.63
15.63
125
15.63
31.25
7.81
15.63
31.25
1.95
3.9
1.95
3.9
7.81
0.48
3.9
125
125
500
62.5
125
15.63
31.25
62.5
7.81
7.81
62.5
125
250
31.25
62.5
7.81
62.5
125
500
62.5
62.5
125
62.5
e
31.25
62.5
250
31.25
62.5
125
125
e
125
125
e
0.97
1.95
0.24
0.48
1.95
31.25
31.25
7.81
7.81
e
62.5
250
125
250
125
250
15.83
AMPH, Amphotricin B; (ꢀ), No activity.

276
S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
135 (17.5), 121 (17.5), 120 (100), 106 (7.3), 104 (4.2), 92 (19.2), 79
(47.5), 65 (14.3), 63 (43.4); Anal. Calcd. for C16H13N3OS (295.37): C,
65.06; H, 4.44; N, 14.23%, Found: C, 65.02; H, 4.41; N, 14.22%.
COCH > H > COCH=CHAr > pyrazoloaryl
3
R
R
1
S
N
N
CH > coumarinyl > acetylaminophenyl
2
3
4.1.2. 3-(2-Pyridin-3-yl-thiazol-4-yl)-chromen-2-one (3)
Brown powder, Yield (55%), mp 246e247 ꢃC; IR (KBr)
nmax/
Fig. 7. Order of antimicrobial activity of 2-(3-pyridyl)-4,5-disubstituted thiazoles.
cmꢀ1: 3055 (CHeAr), 1725 (C]O), 1620 (C]N); 1H NMR (DMSO-
d6): dppm ¼ 7.21e7.56 (m, 4H, CHAr), 7.61 (s, 1H, Thiazole-H5), 7.89
(dd, J ¼ 8 Hz, 5 Hz, 1H, Pyridine-H5), 8.75 (d, J ¼ 5 Hz, 1H, Pyridine-
H4), 8.84 (d, J ¼ 5.0 Hz, 1H, Pyridine-H6), 8.91 (s, 1H, Coumarin-H4),
9.33 (s, 1H, Pyridine-H2); MS m/z (%): 306 (Mþ, 3.5), 286 (28.1), 272
(14.8), 244 (33.0), 226 (87.7), 223 (28.0), 200 (30.3), 178 (14.3), 159
(39.9), 146 (37.2), 131.1 (34.6), 121 (32.2), 120 (37.3), 106 (10.6), 90
(44.9), 86 (100), 78 (14.0), 76 (21.1); Anal. Calcd. for C17H10N2O2S
(306.35): C, 66.65; H, 3.29; N, 9.14%, Found: C, 66.69; H, 3.27; N,
9.11%.
3. Conclusion
In conclusion, the objective of the present study was to syn-
thesize and investigate the antimicrobial activities of some new
2-(3-pyridyl)-4,5-disubstituted thiazoles with the hope of discov-
ering new structures that could be used as potent antimicrobial
agents. Our aim has been verified by the synthesis of five different
groups of structural hybrids comprising basically the 2-(3-pyridyl)
thiazole moiety attached to either acetyl, 3-coumarinyl, 4-
acetylaminophenyl, 3-aryl-propenone-1-yl, and/or 5-aryl-4,5-
dihydro-1H-pyrazol-3-yl. Our results clearly revealed that the
substituted 2-(3-pyridyl)thiazoles exhibited good antimicrobial
activity. The best antimicrobial activity was observed for 5-acetyl-
4.1.3. 3-(4-Methylthiazol-2-yl)-pyridine (4)
Yellow powder, Yield (60%), mp 200e201 ꢃC; IR (KBr)
nmax/
cmꢀ1: 3130e3025 (CHeAr), 2990e2945 (CH-sp3); 1H NMR (DMSO-
d6): dppm ¼ 2.48 (s, 3H, CH3), 7.59 (s, 1H, Thiazole-H5), 7.95 (dd,
J ¼ 8 Hz, 5 Hz, 1H, Pyridine-H5), 8.77 (d, J ¼ 5 Hz, 1H, Pyridine-H4),
8.87 (d, J ¼ 5.0 Hz, 1H, Pyridine-H6), 9.27 (s, 1H, Pyridine-H2); 13C
NMR (DMSO-d6): dppm ¼ 16.7 (CH3), 117.5 (Thiazole-C5), 126.6
(Pyridine-C5), 130.9 (Pyridine-C3), 139.1 (Pyridine-C4), 141.5 (Pyri-
dine-C2), 144.9 (Thiazole-C4), 154.0 (Pyridine-C6), 160.8 (Thiazole-
C2); MS m/z (%): 176 (Mþ, 100), 161 (Mþ ꢀ CH3, 1.5), 150 (3.3), 122
(1.3), 105 (18.8), 88 (8.7), 72 (97.8), 69 (4.4), 51 (7.3); Anal. Calcd. for
C9H8N2S (176.24): C, 61.34; H, 4.58; N, 15.89%, Found: C, 61.32; H,
4.55; N, 15.81%.
4-methyl-2-(3-pyridyl)thiazole
5 followed by 4-methyl-2-(3-
pyridyl)thiazole 4. Increasing the size of the substitutions either
at position 4 or 5 on the thiazole nucleus decreased the anti-
microbial activity.
4. Experimental
Melting points were determined on digital Gallen-Kamp MFB-
595 instrument using open capillary tubes and are uncorrected. IR
spectra were recorded on Schimadzu FTIR 440 spectrometer using
KBr pellets.1H NMR and 13C NMR spectra were recorded on a Bruker
model 500 MHz Ultra Shield NMR spectrometer in DMSO-d6 using
tetramethylsilane (TMS) as an internal standard; chemical shifts are
reported as dppm units. Mass spectra were recorded on Shimadzu
Qp-2010 plus mass spectrometer at 70 eV. The elemental analyses
were carried out at the Microanalytical Center, Cairo University,
Cairo, Egypt. TLC was carried out on Fluka silica gel/TLC-cards
91835. All the chemicals and solvents used were obtained from
Merck.
4.1.4. 1-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-ethanone (5)
Yellow powder, Yield (75%), mp 247e248 ꢃC; IR (KBr)
nmax/
cmꢀ1: 3125e3015 (CHeAr), 2998e2956 (CH-sp3), 1695 (C]O); 1H
NMR (DMSO-d6): dppm ¼ 2.62 (s, 3H, CH3), 2.75 (s, 3H, CH3CO) 7.91
(dd, J ¼ 8 Hz, 5 Hz, 1H, Pyridine-H5), 8.75 (d, J ¼ 5 Hz, 1H, Pyridine-
H4), 8.90 (d, J ¼ 5.0 Hz, 1H, Pyridine-H6), 9.31 (s, 1H, Pyridine-H2);
13C NMR (DMSO-d6): dppm ¼ 17.9 (CH3), 30.3 (CH3), 126.7 (Thiazole-
C5), 129.5 (Pyridine-C5), 133.9 (Pyridine-C3), 138.3 (Pyridine-C4),
143.2 (Pyridine-C2), 150.3 (Thiazole-C4), 158.0 (Pyridine-C6), 163.5
(Thiazole-C2), 190.7 (C]O); MS m/z (%): 218 (Mþ, 96.5), 203
(Mþ ꢀ CH3, 100), 192 (4.9), 175 (30.9), 160 (6.2), 134 (5.1), 105 (25.5),
87 (2.8), 71 (46.9), 64 (50.2), 51 (5.4); Anal. Calcd. for C11H10N2OS
(218.28): C, 60.53; H, 4.62; N, 12.83%, Found: C, 60.51; H, 4.64; N,
12.86%.
4.1. General procedure for the synthesis of compounds (2e5)
To a hot solution of thionicotinamide 1 (0.69 g, 0.005 mol) in
absolute ethanol (20 mL), triethylamine (0.5 mL) was added. To this
mixture, each of, p-chloroacetylacetanilide (1.05 g, 0.005 mol), 3-
bromoacetylcoumarin (1.33 g, 0.005 mol), chloroacetone (0.46 g,
0.005 mol) and 3-chloroacetylacetone (0.67 g, 0.005 mol) was
added and the reaction mixture was refluxed for 8 h. The progress
of the reaction was monitored by TLC. The reaction mixture was
allowed to cool, poured onto ice water (50 mL) and neutralized
with diluted HCl to afford a precipitate that was filtered, washed
with water (2 ꢂ 30 mL), air dried and then recrystallized from the
ethanol.
4.2. General procedure for the synthesis of chalcones 6aee
A
mixture of 1-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-etha-
none (5) (0.654 g, 0.003 mol), appropriate aromatic aldehyde
(0.003 mol) and 10% aqueous sodium hydroxide (15 mL) in meth-
anol (25 mL) was stirred at room temperature for about 3 h. The
resulting solid was filtered off, rinsed with water, dried, and crys-
tallized from ethanol.
4.2.1. 1-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-3-phenyl-
4.1.1. N-[4-(2-Pyridin-3-yl-thiazol-4-yl)-phenyl]-acetamide (2)
propenone (6a)
Yellow powder, Yield (73%), mp 251e252 ꢃC; IR (KBr)
n
max/
Yellow powder, Yield (78%), mp 150e151 ꢃC; IR (KBr) max/cmꢀ1
n :
cmꢀ1: 3190 (NH), 3055 (CHeAr), 2950, 2925 (CH-sp3), 1680 (C]O),
1595 (C]N); 1H NMR (DMSO-d6): dppm ¼ 2.21 (s, 3H, CH3), 7.26 (d,
J ¼ 7.8 Hz, 2H, 2CHAr), 7.42 (d, J ¼ 7.8 Hz, 2H, 2CHAr), 7.56 (s, 1H,
Thiazole-H5), 7.91 (dd, J ¼ 8 Hz, 5.5 Hz, 1H, Pyridine-H5), 8.41 (s, 1H,
NH), 8.72 (d, J ¼ 5.5 Hz, 1H, Pyridine-H4), 8.81 (d, J ¼ 5.0 Hz, 1H,
Pyridine-H6), 9.27 (s, 1H, Pyridine-H2); MS m/z (%): 295 (Mþ, 2.7),
253 (Mþ ꢀ COCH3, 2.8), 222 (2.9), 177 (20.5), 162 (60.8), 149 (1.8),
3032 (CHeAr), 2936, 2887 (CH-sp3), 1654 (C]O), 1605 (C]C); 1H
NMR (DMSO-d6): dppm ¼ 2.80 (s, 3H, CH3), 7.37 (d, J ¼ 15.0 Hz, 1H,
CH]), 7.47e7.60 (m, 5H, CHAr), 7.75 (d, J ¼ 15.0 Hz, 1H, CH]), 7.85
(dd, J ¼ 7.8 Hz, 5 Hz,1H, Pyridine-H5), 8.39 (d, J ¼ 5 Hz,1H, Pyridine-
H4), 8.74 (d, J ¼ 5.0 Hz,1H, Pyridine-H6), 9.20 (s,1H, Pyridine-H6); 13
C
NMR (DMSO-d6): dppm ¼ 18.2 (CH3), 124.3 (Thiazole-C5), 124.4
(2CHAr), 128.1 (CH]), 128.9 (2CHAr), 129.0 (Pyridine-C5), 130.9

S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
277
(CHAr), 132.3 (CAr), 133.9 (Pyridine-C3), 134.0 (Pyridine-C4), 144.0
(CH]), 147.1 (Pyridine-C2), 151.8 (Thiazole-C4), 158.9 (Pyridine-C6),
165.5 (Thiazole-C2), 182.2 (C]O); MS m/z (%): 306 (Mþ, 100), 305
(Mþ ꢀ H, 44.5), 289 (4.1), 273 (6.6), 263 (3.9), 229 (41.5), 215 (10.3),
202 (22.0), 175 (4.9), 159 (1.8), 131 (26.0), 115 (4.3), 103 (41.0), 91
(5.3), 77 (31.7), 51 (8.9); Anal. Calcd. for C18H14N2OS (306.39):
C,70.56; H, 4.61; N, 9.14%, Found: C, 70.51; H, 4.57; N, 9.11%.
(Pyridine-C4), 134.0 (Pyridine-C2), 134.7 (CH]), 134.8 (Thiazole-C4),
147.2 (Pyridine-C6), 151.9 (CFAr), 159.4 (Thiazole-C2), 165.8 (CFAr),
181.8 (C]O); MS m/z (%): 342 (Mþ, 100), 341 (Mþ ꢀ H, 26.3), 325
(4.8), 306 (4.9), 238 (19.9), 229 (28.3), 218 (27.6), 203 (34.6), 175
(16.2), 167 (26.5), 139 (39.5), 119 (46.1), 105 (36.9), 97 (22.6), 71
(75.5); Anal. Calcd. for C18H12F2N2OS (342.37): C, 63.15; H, 3.53; N,
8.18%, Found: C, 63.11; H, 3.50; N, 8.15%.
4.2.2. 3-(4-Methoxyphenyl)-1-(4-methyl-2-pyridin-3-yl-thiazol-5-
4.3. General procedure for the synthesis of 5-aryl-4,5-dihydro-1H-
yl)-propenone (6b)
pyrazoles 7aee
Yellow powder, Yield (91%), mp 155e156 ꢃC; IR (KBr)
nmax/
cmꢀ1: 3040 (CHeAr), 2915, 2887 (CH-sp3),1655 (C]O),1600 (C]C);
1H NMR (DMSO-d6): dppm ¼ 2.79 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.04
(d, J ¼ 6.8 Hz, 2H, 2CHAr), 7.35 (d, J ¼ 15.5 Hz, 1H, CH]), 7.58 (m, 1H,
Pyridine-H5), 7.72 (d, J ¼ 15.5 Hz, 1H, CH]), 7.82 (d, J ¼ 6.8 Hz, 2H,
2CHAr), 8.38 (d, J ¼ 5 Hz, 1H, Pyridine-H4), 8.73 (d, J ¼ 4.9 Hz, 1H,
Pyridine-H6), 9.19 (s, 1H, Pyridine-H2); 13C NMR (DMSO-d6):
dppm ¼ 18.2 (CH3), 55.4 (OCH3), 114.6 (CH]), 122.2 (Pyridine-C4),
124.3 (Thiazole-C5), 126.6 (2CHAr), 128.2 (2CHAr), 130.9 (CAr), 132.6
(CHAr),133.9 (CAr),144.2 (Pyridine-C5),147.1 (CH]),151.8 (Pyridine-
C2), 158.6 (Thiazole-C4), 161.7 (Pyridine-C6), 165.2 (Thiazole-C2),
182.1 (C]O); MS m/z (%): 336 (Mþ, 100), 335 (36.6), 321 (Mþ ꢀ CH3,
8.1), 305 (Mþ ꢀ OCH3, 21.0), 293 (6.1), 278 (1.3), 232 (47.1), 217 (21.1),
202 (8.3), 189 (3.7), 161 (25.1), 145 (2.9), 133 (28.0), 121 (85.2), 108
(14.9), 90 (12.5), 80 (42.1), 64 (20.7); Anal. Calcd. for C19H16N2O2S
(336.42): C, 67.84; H, 4.79; N, 8.33%, Found: C, 67.77; H, 4.75; N,
8.29%.
A solution of the appropriate chalcones 6aee (0.3 mmol) and
hydrazine hydrate (0.6 mmol) in ethanol (15 mL) was refluxed for
3 h. The reaction mixture was cooled and kept at 0 ꢃC overnight.
The resulting solid was collected by filtration and recrystallized
from ethanol to give compounds 7aee.
4.3.1. 3-[4-Methyl-5-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-
thiazol-2-yl]-pyridine (7a)
Canary yellow powder, Yield (68%), mp 163e164 ꢃC; IR (KBr)
n
max/cmꢀ1: 3215 (NH), 3037 (CHeAr), 2976 (CH-sp3), 1592 (C]N);
1H NMR (DMSO-d6): dppm ¼ 2.58 (s, 3H, CH3), 2.98e3.00 (m, 1H,
Pyrazoline-H4), 3.56e3.62 (m, 1H, Pyrazoline-H4), 4.90 (dd, J ¼ 12.0,
5.6 Hz, 1H, Pyrazoline-H5), 7.21e7.41 (m, 5H, CHAr), 7.53 (s, 1H, NH),
7.82 (m, 1H, Pyridine-H5), 8.27 (d, J ¼ 5 Hz,1H, Pyridine-H4), 8.65 (d,
J ¼ 4.9 Hz, 1H, Pyridine-H6), 9.09 (s, 1H, Pyridine-H2); 13C NMR
(DMSO-d6): dppm ¼ 16.9 (CH3), 42.4 (Pyrazoline-C4), 64.3 (Pyrazo-
line-C5), 124.2 (Thiazole-C5), 126.6 (2CHAr), 126.9 (Pyridine-C5),
127.5 (2CHAr), 128.4 (Pyridine-C3), 128.8 (CHAr), 133.2 (Pyridine-C4),
141.3 (CAr), 142.3 (Pyrazoline-C3), 146.6 (Thiazole-C4), 150.1 (Pyri-
dine-C2), 150.7 (Pyridine-C6), 160.2 (Thiazole-C2); Anal. Calcd. for
C18H16N4S (320.42): C, 67.47; H, 5.03; N, 17.49%, Found: C, 67.45; H,
5.01; N, 17.52%.
4.2.3. 3-(4-Chlorophenyl)-1-(4-methyl-2-pyridin-3-yl-thiazol-5-
yl)-propenone (6c)
Yellowish white powder, Yield (85%), mp 155e156 ꢃC; IR (KBr)
n
max/cmꢀ1: 3045 (CHeAr), 2965, 2915 (CH-sp3), 1658 (C]O), 1598
(C]C); 1H NMR (DMSO-d6): dppm ¼ 2.72 (s, 3H, CH3), 7.29 (d,
J ¼ 7.0 Hz, 2H, 2CHAr), 7.39 (d, J ¼ 15 Hz, 1H, CH]), 7.56 (dd, J ¼ 7.8,
5 Hz, 1H, Pyridine-H5), 7.75 (d, J ¼ 15 Hz, 1H, CH]), 7.86 (d,
J ¼ 7.0 Hz, 2H, 2CHAr), 8.43 (d, J ¼ 5 Hz, 1H, Pyridine-H4), 8.78 (d,
J ¼ 5 Hz,1H, Pyridine-H6), 9.23 (s, 1H, Pyridine-H2); MS m/z (%): 340
(Mþ, 100), 399 (Mþ ꢀ H, 36.3), 323 (4.9), 305 (21.3), 277 (3.3), 229
(45.0), 215 (20.9), 203 (24.3), 175 (16.2), 165 (20.4), 139 (36.7), 122
(12.4), 102 (37.9), 78 (15.2), 71 (49.2), 64 (33.2), 51 (16.4); Anal.
Calcd. for C18H13ClN2OS (340.83): C, 63.43; H, 3.84; N, 8.22%, Found:
C, 63.40; H, 3.79; N, 8.21%.
4.3.2. 3-{5-[5-(4-Methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]-
4-methyl-thiazol-2-yl}-pyridine (7b)
Canary yellow powder, Yield (72%), mp 153e154 ꢃC; IR (KBr)
n
max/cmꢀ1: 3220 (NH), 3014 (CHeAr), 2981 (CH-sp3), 1589 (C]N);
1H NMR (DMSO-d6): dppm ¼ 2.58 (s, 3H, CH3), 3.04 (dd, J ¼ 11.8,
5.0 Hz, 1H, Pyrazoline-H4), 3.61 (dd, J ¼ 7.5, 5.0 Hz, 1H, Pyrazoline-
H4), 3.92 (s, 3H, OCH3), 4.96 (dd, J ¼ 11.8, 5 Hz, 1H, Pyrazoline-H5),
7.18 (d, J ¼ 6.8 Hz, 2H, 2CHAr), 7.56 (s, 1H, NH), 7.69 (d, J ¼ 6.8 Hz, 2H,
2CHAr), 7.86 (m, 1H, Pyridine-H5), 8.32 (d, J ¼ 4.9 Hz, 1H, Pyridine-
H4), 8.73 (d, J ¼ 4.9 Hz, 1H, Pyridine-H6), 9.21 (s, 1H, Pyridine-H2);
MS m/z (%): 350 (Mþ, 20.7), 312 (62.0), 279 (72.4), 250 (100), 224
(59.2), 219 (64.9), 204 (60.9), 193 (90.8), 162 (60.9), 146 (64.9), 121
(14.9), 90 (72.9), 79 (70.1); Anal. Calcd. for C19H18N4OS (350.44): C,
65.12; H, 5.18; N, 15.99%, Found: C, 65.09; H, 5.14; N, 16.03%.
4.2.4. 1-(4-Methyl-2-pyridin-3-yl-thiazol-5-yl)-3-(2-nitrophenyl)-
propenone (6d)
Buff flaks, Yield (55%), mp 132e133 ꢃC; IR (KBr) max/cm-1:
n
3005 (CHeAr), 2979, 2885 (CH-sp3),1660 (C]O),1600 (C]C),1520,
1350 (NO2); 1H NMR (DMSO-d6): dppm ¼ 2.75 (s, 3H, CH3), 7.16e7.43
(m, 4H, CHAr), 7.49 (d, J ¼ 15.2 Hz, 1H, CH]), 7.59 (dd, J ¼ 8, 4.8 Hz,
1H, Pyridine-H5), 7.81 (d, J ¼ 15.2 Hz, 1H, CH]), 8.49 (d, J ¼ 4.8 Hz,
1H, Pyridine-H4), 8.89 (d, J ¼ 5 Hz, 1H, Pyridine-H6), 9.18 (s, 1H,
Pyridine-H2); Anal. Calcd. for C18H13N3O3S (351.39): C, 61.53; H,
3.73; N, 11.96%, Found: C, 61.51; H, 3.76; N, 11.98%.
4.3.3. 3-{5-[5-(4-Chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl]-4-
methyl-thiazol-2-yl}-pyridine (7c)
Canary yellow powder, Yield (62%), mp 192e193 ꢃC; IR (KBr)
n
max/cmꢀ1: 3225 (NH), 3045, 3030 (CHeAr), 2920 (CH-sp3), 1590
(C]N), 1565 (C]C); 1H NMR (DMSO-d6): dppm ¼ 2.51 (s, 3H, CH3),
2.96 (dd, J ¼ 11, 5.4 Hz, 1H, Pyrazoline-H4), 3.59 (dd, J ¼ 11, 7.6 Hz,
1H, Pyrazoline-H4), 4.93 (dd, J ¼ 11, 5.4 Hz, 1H, Pyrazoline-H5),
7.35e7.45 (m, 4H, CHAr), 7.50 (s, 1H, NH), 7.84 (d, J ¼ 3.0 Hz, 1H,
Pyridine-H4), 8.25 (dd, J ¼ 5, 3 Hz,1H, Pyridine-H5), 8.64 (d, J ¼ 5 Hz,
1H, Pyridine-H6), 9.09 (s, 1H, Pyridine-H2); 13C NMR (DMSO-d6):
dppm ¼ 16.9 (CH3), 42.3 (Pyrazoline-C4), 63.5 (Pyrazoline-C5), 124.2
(Thiazole-C5), 127.3 (2CHAr), 128.5 (Pyridine-C5), 128.7 (2CHAr),
128.9 (CAr), 131.7 (Pyridine-C3), 133.2 (Pyridine-C4), 141.4 (CAr),
142.5 (Pyrazoline-C3), 146.6 (Thiazole-C4), 150.2 (Pyridine-C2),
150.7 (Pyridine-C6), 160.3 (Thiazole-C2); MS m/z (%): 354 (Mþ, 100),
339 (2.6), 323 (4.1), 319 (2.5), 290 (2.1), 243 (20.5), 226 (2.2), 215
4.2.5. 3-(2,4-Difluorophenyl)-1-(4-methyl-2-pyridin-3-yl-thiazol-
5-yl)-propenone (6e)
Yellowish white powder, Yield (72%), mp 162e163 ꢃC; IR (KBr)
n
max/cmꢀ1: 3100, 3060 (CHeAr), 2987, 2877 (CH-sp3),1652 (C]O),
1598 (C]C); 1H NMR (DMSO-d6): dppm ¼ 2.78 (s, 3H, CH3), 7.22e
7.41 (m, 2H, CHAr), 7.49 (d, J ¼ 15.5 Hz, 1H, CH]), 7.58 (s, 1H,
CHAr), 7.71 (d, J ¼ 15.5 Hz, 1H, CH]), 8.07 (m, 1H, Pyridine-H5), 8.37
(d, J ¼ 5 Hz, 1H, Pyridine-H4), 8.73 (d, J ¼ 4.8 Hz, 1H, Pyridine-H6),
9.17 (s, 1H, Pyridine-H2); 13C NMR (DMSO-d6): dppm ¼ 18.2 (CH3),
104.5 (CHAr), 112.5 (CHAr), 118.7 (CAr), 124.3 (Thiazole-C5), 126.3
(Pyridine-C5), 128.1 (CH]), 131.5 (Pyridine-C3), 131.7 (CHAr), 132.2

278
S. Bondock et al. / European Journal of Medicinal Chemistry 62 (2013) 270e279
(14.5), 202 (3.0), 177 (2.5), 138 (6.9), 105 (8.7), 89 (2.4), 71 (6.5), 59
(2.6); Anal. Calcd. for C18H15ClN4S (354.86): C, 60.92; H, 4.26; N,
15.79%, Found: C, 60.96; H, 4.28; N, 15.83%.
technique, were further evaluated for their minimal inhibitory
concentrations (MICs).
5.1. Minimal inhibitory concentration (MIC) measurement
4.3.4. 3-{4-Methyl-5-[5-(2-nitrophenyl)-4,5-dihydro-1H-pyrazol-
3-yl]-thiazol-2-yl}-pyridine (7d)
The microdilution susceptibility test in MüllereHinton Broth
(Oxoid) and Subouraud Liquid Medium (Oxoid) was used for the
determination of antibacterial and antifungal activity, respectively.
Stock solutions of the tested compounds, ampicillin, gentamycin
and amphotricin B were prepared in DMF at concentrations
Yellowish brown powder, Yield (60%), mp 123e124 ꢃC; IR (KBr)
n
max/cmꢀ1: 3218 (NH), 3040, 3015 (CHeAr), 2976 (CH-sp3), 1595
(C]N), 1528, 1357 (NO2); 1H NMR (DMSO-d6): dppm ¼ 2.62 (s, 3H,
CH3), 2.90 (dd, J ¼ 11.4, 5.0 Hz, 1H, Pyrazoline-H4), 3.52 (dd, J ¼ 11.4,
7.2 Hz, 1H, Pyrazoline-H4), 4.98 (dd, J ¼ 11.4, 5.0 Hz, 1H, Pyrazoline-
H5), 7.28e7.49 (m, 4H, CHAr), 7.54 (s, 1H, NH), 7.81 (d, J ¼ 4.8 Hz, 1H,
Pyridine-H4), 8.31 (dd, J ¼ 4.8, 4.1 Hz, 1H, Pyridine-H5), 8.69 (d,
J ¼ 4.8 Hz, 1H, Pyridine-H6), 9.23 (s, 1H, Pyridine-H2); Anal. Calcd.
for C18H15N5O2S (365.42): C, 59.17; H, 4.14; N, 19.17%, Found: C,
59.13; H, 4.12; N, 19.14%.
1000
broth (Difco) to prepare serial twofold dilutions in the range of
500e0.007
g/mL 10 mL of the broth containing about 106 CFU/mL
mg/mL. Each stock solution was diluted with standard method
m
of test bacteria was added to each well of 96-well microtiter plate.
The sealed microplates were incubated at 37 ꢃC for 24 h for anti-
bacterial activity and at 25 ꢃC for 48 h for antifungal activity in
a humid chamber. At the end of the incubation period, the minimal
inhibitory concentrations (MIC) values were recorded as the lowest
concentrations of the substance that inhibited the growth of the
tested organisms judged by the absence of visible turbidity. Control
experiments with DMF and uninoculated media were run parallel
to the test compounds under the same conditions.
4.3.5. 3-{5-[5-(2,4-Difluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl]-
4-methyl-thiazol-2-yl}-pyridine (7e)
Canary yellow powder, Yield (65%), mp 125e126 ꢃC; IR (KBr)
n
max/cmꢀ1: 3200 (NH), 3050 (CHeAr), 1590 (C]N); 1H NMR
(DMSO-d6): dppm ¼ 2.51 (s, 3H, CH3), 2.79 (dd, J ¼ 12.1, 5.8 Hz, 1H,
Pyrazoline-H4), 3.25 (dd, J ¼ 7.8, 5.8 Hz, 1H, Pyrazoline-H4), 5.40
(dd, J ¼ 12.1, 7.8 Hz, 1H, Pyrazoline-H5), 6.90e7.60 (m, 4H,
3CHAr þ NH), 8.30e8.45 (m, 1H, Pyridine-H5), 8.27 (d, J ¼ 5.8 Hz,1H,
Pyridine-H4), 8.74 (d, J ¼ 5.0 Hz, 1H, Pyridine-H6), 9.14 (s, 1H, Pyr-
idine-H2); 13C NMR (DMSO-d6): dppm ¼ 18.3 (CH3), 50.6 (Pyrazo-
line-C4), 62.7 (Pyrazoline-C5), 124.4 (Thiazole-C5), 128.2 (CHAr),
129.4 (CHAr), 131.7 (CHAr), 132.2 (Pyridine-C5), 133.8 (Pyridine-C3),
134.2 (Pyridine-C4), 134.9 (CAr), 146.2 (Pyrazoline-C3), 146.9 (CAr),
147.1 (CAr), 150.2 (Thiazole-C4), 151.5 (Pyridine-C2), 151.7 (Pyridine-
C6), 159.4 (Thiazole-C2); MS m/z (%): 356 (Mþ, 16.0), 355 (Mþ ꢀ H,
25.6), 354 (100), 342 (68.8), 325 (4.8), 250 (1.5), 229 (17.6), 220
(17.7), 203 (17.8), 189 (4.2), 141 (18.6), 119 (28.2), 105 (26.9), 71
(30.7), 69 (12.2), 51 (8.2); Anal. Calcd. for C18H14F2N4S (356.40): C,
60.66; H, 3.96; N, 15.72%, Found: C, 60.69; H, 3.98; N, 15.75%.
Acknowledgments
The authors are thankful to the Deanship of Scientific Research
at King Khalid University for the financial support of the project no.
(KKU-SCII-12-092).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.12.050.
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