Synthesis and evaluation of some new 5-(hetaryl)thiazoles as potential antimicrobial agents

Article abstract of DOI:10.1080/00397911.2017.1412465

In continuing our efforts to find new effective antimicrobial agents for overcoming the problem of microbial resistance, a new series of functionalized 5-hetarylthiazoles have been designed and synthesized starting from readily accessible 1-(2-allylamino-4-methylthiazol-5-yl)ethanone (3). The structures of newly synthesized compounds were confirmed by elemental analyses, spectral data, and chemical transformations. The synthesized compounds were evaluated in vitro for their antimicrobial activity against some human pathogenic bacterial and fungal strains. The compounds 7, 18, and 24 exhibited higher antibacterial activity with minimum inhibitory concentration (MIC) values ranging from (0.03–0.06 μg/mL) than ampicillin (MIC, 0.12 μg/mL) against Streptococcus pneumoniae. Whereas compounds 4, 22, and 24 revealed higher antifungal potency than amphotericin B against Aspergillus fumigatus. The structure and antimicrobial activity relationship was also discussed.

Full text of DOI:10.1080/00397911.2017.1412465

Synthetic Communications
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Synthesis and evaluation of some new 5-
(hetaryl)thiazoles as potential antimicrobial agents
Samir Bondock & Ahmed M. Fouda
To cite this article: Samir Bondock & Ahmed M. Fouda (2018): Synthesis and evaluation of
some new 5-(hetaryl)thiazoles as potential antimicrobial agents, Synthetic Communications, DOI:
10.1080/00397911.2017.1412465
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SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1412465
Synthesis and evaluation of some new 5-(hetaryl)thiazoles as
potential antimicrobial agents
Samir Bondocka,b
and Ahmed M. Foudaa
aChemistry Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia; bChemistry
Department, Faculty of Science, Mansoura University, Mansoura, Egypt
ABSTRACT
ARTICLE HISTORY
Received 13 October 2017
In continuing our efforts to find new effective antimicrobial agents for
overcoming the problem of microbial resistance, a new series of
functionalized 5-hetarylthiazoles have been designed and synthesized
starting from readily accessible 1-(2-allylamino-4-methylthiazol-5-yl)
ethanone (3). The structures of newly synthesized compounds were
confirmed by elemental analyses, spectral data, and chemical
transformations. The synthesized compounds were evaluated in vitro
for their antimicrobial activity against some human pathogenic
bacterial and fungal strains. The compounds 7, 18, and 24 exhibited
higher antibacterial activity with minimum inhibitory concentration
(MIC) values ranging from (0.03–0.06 µg/mL) than ampicillin (MIC,
0.12 µg/mL) against Streptococcus pneumoniae. Whereas compounds
4, 22, and 24 revealed higher antifungal potency than amphotericin B
against Aspergillus fumigatus. The structure and antimicrobial activity
relationship was also discussed.
KEYWORDS
Antimicrobial activity;
azoloazine; bithiazolyl
hydrazine; pyrazoline;
thiazole
GRAPHICAL ABSTRACT
CONTACT Samir Bondock
Bondock@mans.edu.eg
Chemistry Department, Faculty of Science, King Khalid University,
P.O. Box 9004, Abha 61413, Saudi Arabia.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

2
S. BONDOCK AND A. M. FOUDA
Introduction
The synthesis of innovative antimicrobial agents with new structure and mode of action
remains the principal objective of researchers for overcoming the problem of microbial
resistance gained by microorganism to the approved antimicrobial agents.[1] Thiazole is
well documented as one of the most prevalent core structures in drug design and discovery
of innovative therapeutic agents.[2] Previous reports have established that thiazole deriva-
tives possess diverse biological properties including antimicrobial,[3] antitubercular,[4]
antiviral,[5] anticancer,[6] anticonvulsant,[7] and anti-inflammatory activities.[8] Moreover,
they were used also for treatment of diabetes and Alzheimer’s diseases.[9] Among
substituted thiazoles, 5-acetylthiazoles represent a fertile commencing material for the
synthesis of plentiful numbers of bioactive heterocyclic compounds. The progress of the
chemistry of 5-acetylthiazoles was recently reviewed by us.[10] There are some routes
published for the synthesis of 5-aceylthiazoles. The easiest and most applicable synthetic
strategy to achieve 5-aceylthiazoles is the Hantzsch reaction of substrates bearing N-C-S
unit with 3-chloro-2,4-pentanedione.[10] Chalcones, 1,3-diarylprop-2-en-1-ones, and their
heterocyclic analogues are versatile synthons for the synthesis of five- and six-membered
nitrogen heterocyclic compounds, such as pyrroles, indoles, isoxazoles, imidazoles,
pyrazoles, indazoles, triazoles, tetrazoles, pyridines, and pyrimidines.[11] This class of
compounds has been also reported to possess various chemotherapeutic effects including
anti-tuberculosis,[12] antifungal,[13] in addition to antitumor activities for which different
mechanisms of action have been proposed.[14]
On the other hand, pyrazolines represent a fascinating class of heterocycles due to their
varied synthetic use and potent biological activities, such as antimicrobial,[15] antiviral,[16]
anti-inflammatory, analgesic,[17,18] antidepressant,[19] anticonvulsant,[20] antitubercular,[21]
antiamoebic,[22] and anticancer activities.[23]
In view of the above-mentioned findings, and as a continuation of our great efforts to
find new candidates,[24–33] which are decisive in designing new effective, selective, and less
toxic antimicrobial agents, we report herein the regioselective synthesis and antimicrobial
evaluation of some novel functionalized 5-heteroarylthiazoles.
Results and discussion
Chemistry
The commencing material, 1-(2-allylamino-4-methylthiazol-5-yl)ethanone (3),[34] was
prepared by applying the Hantszch reaction of 1-allylthiourea (1) with 3-chloro-2,4-
pentanedione (2) in ethanol, under reflux, and in the presence of a catalytic amount of
triethylamine. The Claisen–Schmidt reaction of 1-(2-allylamino-4-methylthiazol-5-yl)-
ethanone (3) with 4-chlorobenzaldehyde in an aqueous methanolic solution of potassium
hydroxide at room temperature afforded a sole product as a yellow powder identified as
1-(2-allylamino-4-methylthiazol-5-yl)-3-(4-chlorophenyl)prop-2-en-1-one (4) in good
yield (Scheme 1). The structure of compound 4 was inferred from elemental analysis
and spectral data. The IR spectrum of 4 showed absorption bands at 3200, 1632,
1600 cm−1 characteristic for a secondary amino group (NH), α,β-unsaturated carbonyl
1
=
group, and conjugated olefinic C C group, respectively. Its H-NMR spectrum displayed
besides the expected vinyl and aromatic signals, two singlet signals at δ 2.55, 8.74 ppm

SYNTHETIC COMMUNICATIONS®
3
Scheme 1. Synthesis of 5-(2-pyrazolin-3-yl)thiazoles 5–8.
due to a methyl protons and NH proton, respectively, and a triplet signal at 3.92 ppm
=
assignable to a methylene proton. The two protons of the ethylenic group (CH CH)
resonate at δ 7.33, 7.54 ppm with coupling constant (J ¼ 16.0 Hz) confirming the
E-configuration of the formed thiazolyl chalcone 4. The 13C-NMR spectrum of compound
4 revealed the presence of 14 carbon signals, the most important carbon signals resonate at
δ 19.0, 46.7, 125.6, 134.5, 179.6 ppm characteristic for CH3, NCH2, ethylenic group
=
=
(CH CH), and a conjugated C O, respectively. The mass spectrum of 4 showed a molecu-
lar ion peak at m/z ¼ 318 (Mþ) and isotopic peak [M þ 2]þ at m/z ¼ 320 in a ratio of 3:1
which supported a molecular formula (C16H15ClN2OS) and confirmed the presence of
chlorine atom.
The α,β-unsaturated carbonyl system of thiazolyl chalcone 4 possesses two electrophilic
reactive sites (C-1 and C-3) allowing them to share in addition reactions through attack to
the carbonyl group (1,2-addition) or involving the β-carbon (1,4-addition), leading to the
synthesis of promising bioactive heterocyclic compounds. In this regard, we investigated
the site selectivity of the nucleophilic addition of nitrogen containing 1,2-binucleophiles
to thiazolyl chalcone to attain some new functionalized 5-(2-pyrazolin-3-yl)thiazoles with
anticipated antimicrobial activity. Thus, cyclocondensation of thiazolyl chalcone 4 with
each of hydrazine hydrate and phenylhydrazine in boiling ethanol afforded, in each case,
a single product, identified as 2-allylamino-4-methyl-5-(5-(4-chlorophenyl)-2-pyrazolin-
3-yl)thiazoles (5) and 2-allylamino-4-methyl-5-(5-(4-chlorophenyl)-1-phenyl-2-pyrazolin-
3-yl)thiazoles (6).
In a similar manner, interacting of 4 with each of thiosemicarbazide and 4-phenylthio-
semicarbazide in ethanol, under reflux, and in the presence of equimolar amount of
sodium hydroxide gave the regioselective 2-allylamino-4-methyl-5-(5-(4-chlorophenyl)-1-
thiocarbamoyl-2-pyrazolin-3-yl)thiazole (7) and 2-allylamino-4-methyl-5-(5-(4-chlorophe-
nyl)-1-(phenylthiocarbamoyl)-2-pyrazolin-3-yl)thiazole (8), respectively (Scheme 1). The
chemical structures of compounds 5–8 were elucidated on the basis of their spectral data
and elemental analyses. The IR spectrum of compound 7, as an example, showed strong
absorption bands at 3426, 3257, 3171, 1622, 1604, 1309 cm−1 characteristic for NH,
1
=
=
NH2, C C, and C S groups, respectively. Its H-NMR spectrum displayed a singlet signal
resonate at δ 2.27 and a triplet signal at 3.93 ppm assignable to methyl and methylene pro-
tons. There is also two singlets resonate at δ 7.89, 8.42 ppm and exchangeable with D2O
due to the NH and NH2 protons, respectively. The ABX spin system of pyrazoline ring

4
S. BONDOCK AND A. M. FOUDA
1,2
1,3
residue resonates at
δ
3.00 (dd,
J
¼ 15.0 Hz,
J
¼ 9.75 Hz), 3.37 (dd,
AX
1,3
AB
1,2
1,3
1,3
J
¼ 15.0 Hz,
J
¼ 6.5 Hz), and 4.00 (dd,
J
¼ 9.75 Hz,
J
BX
¼ 6.5 Hz). The pro-
AB
BX
AX
tons of vinyl group displayed also around δ 5.14 (dd, 1,2J ¼ 1.7 Hz, 1,3J ¼ 10.5 Hz), 5.25 (dd,
1,2J ¼ 1.7 Hz, 1,3J ¼ 17.0 Hz), 5.89–5.94 (m) owing to the methylene and methine protons,
respectively. The 13C-NMR spectrum of compound 7 revealed the presence of 15 carbon
signals. The Sp3 hybridized carbon signals resonate at δ 17.4, 44.1, 46.3, 62.2 ppm
characteristic for methyl carbon pyrazoline-C-4, methylene carbon, and pyrazoline-C-5,
respectively. The Sp2 hybridized carbon signals of the vinyl group resonate at δ 116.0,
134.6 ppm due to the methylene and methine carbons. The highly downfield signals
appeared at δ 168.3, 174.6 ppm were ascribed to the carbon of thiazole-C-2 and thiocarbo-
nyl carbon, respectively. Further, the mass spectrum of 7 exhibited a molecular ion peak at
m/z ¼ 391 (Mþ) which is compatible with a molecular formula (C17H18ClN5S2).
The proposed mechanism for the formation of compounds 5–8 is depicted in Scheme 2.
As shown in Scheme 2, there are two possible pathways for the addition of hydrazine
derivatives to chalcone. The first pathway involves the nucleophilic addition of a more
basic NH2 group to a carbonyl group of chalcone 4 (1,2-addition) followed by tandem
elimination of water to give the non-isolable hydrazone intermediate B which in turn
cyclizes to pyrazolines 5–8 through Michael-type addition of a secondary amino group
to the activated β-carbon of hydrazone B. The second pathway requires the 1,4-addition
of NH2 group to the activated β-carbon of chalcone 4 to give intermediates (I) and (II)
those undergo cyclization through intramolecular nucleophilic addition of a secondary
amino group to a carbonyl group to give intermediate (III) followed by tandem elimination
of a water molecule to afford pyrazolines (IV). The regioisomeric pyrazolines (IV) was
1
excluded on the basis of spectral data (IR, H-NMR, 13C-NMR).
The presence of a versatile thiocarbamoyl group at position 1 in pyrazoline 7 has
encouraged us to convert this group to valuable bioactive functionalized 5-(1-(thiazol-2-
yl)-2-pyrazolin-3-yl)thiazole derivatives. Thus, refluxing of 7 with each of phenacyl bro-
mide and 4-fluorophenacyl bromide in boiling ethanol containing a catalytic amount of
Scheme 2. Proposed mechanism for the formation of pyrazolines 5–8.

SYNTHETIC COMMUNICATIONS®
5
triethylamine under Hantzsch thiazole reaction condition afforded 2-allylamino-4-methyl-
5-(5-(4-chlorophenyl)-1-(4-phenylthiazol-2-yl)-2-pyrazolin-3-yl)thiazole (9) and
2-allylamino-4-methyl-5-(5-(4-chlorophenyl)-1-(4-(4-flurophenyl)thiazol-2-yl)-2-pyrazolin-
3-yl)thiazole (10), respectively. The structures of the later products 9–10 were confirmed
on the basis of elemental analyses and spectral data as well as chemically elucidated
through an alternative synthesis by the one-pot reaction of 4 with thiosemicarbazide
and α-bromoketones in boiling ethanol containing a catalytic amount of conc. HCl
(Scheme 3). The IR spectrum of 9, as an example, showed the disappearance of NH2
=
and C S functional groups those exist in its precursor 7 and revealed the stretching bands
at 3200, 1621, 1600 cm−1 due to NH, C C, and conjugated C N groups, respectively. The
1H-NMR spectrum of compound 9 showed besides the expected signals of NH, vinyl and
aromatic protons, singlet signal at δ 2.31 ppm for a methyl group, a triplet signal at δ
3.91 ppm for a methylene group, and a singlet signal at δ 7.30 ppm for a proton of thiazole
ring residue. The spectrum displayed also the presence of three doublet of doublets signals
resonate around δ 3.28 (dd, J ¼ 16.0, 12.0 Hz), 4.06 (J ¼ 16.0, 7.0 Hz), and 5.58 (dd,
J ¼ 12.0, 7.0 Hz) ppm owing to the protons of pyrazoline ring residue H-4A, H-4B, and
H-5, respectively. Its 13C-NMR spectrum revealed the presence of 21 carbon signals. The
most important carbon signals resonate at δ 17.2, 44.8, 46.2, 63.6, 167.6 ppm characteristic
for the carbons of CH3, pyrazoline-C-4, NCH2, pyrazoline-C-5, and thiazole-C-2, respect-
ively. The mass spectrum of 9 exhibited a molecular ion peak at m/z ¼ 491 (Mþ) which
consistent with a molecular formula (C25H22ClN5S2).
=
=
The foregoing results prompted us to investigate the reactivity of thiazolyl chalcone 4
toward hydroxyamine, gaunidine and aminoazoles to achieve azole, azine, and azoloazine
substituted thiazoles. Thus, the base catalyzed cyclocondensation of 4 with hydroxylamine
hydrochloride in ethanol containing sodium acetate as a basic medium, under reflux,
afforded a single product identified as 2-allylamino-5-[5-(4-chlorophenyl)-4,5-dihydroi-
soxazol-3-yl]-4-methylthiazole (11). Also, when chalcone 4 was allowed to react with
guanidine hydrochloride in boiling ethanol and in the presence of sodium hydroxide gave
the respective 2-allylamino-5-[2-amino-6-(4-chlorophenyl)pyrimidin-4-yl]-4-methylthia-
zole (12) (Scheme 4). The chemical structures of compounds 11 and 12 were inferred from
their correct microanalyses and spectral data (see experimental part).
Scheme 3. Synthesis of 5-(1-(thiazol-2-yl)-2-pyrazolin-3-yl)thiazoles 9–10.

6
S. BONDOCK AND A. M. FOUDA
Scheme 4. Synthesis of 5-hetarylthiazoles 11–14.
On the other hand, the reaction of 4 with each of 3-amino-1H-1,2,4-triazole and
2-aminobenzimidazole as 1,3-binucleophiles in DMF under reflux afforded the respective
thiazole substituted with [1,2,4]triazolo[1,5-a]pyrimidine 13 and pyrimido[1,2-a]benzimi-
dazole 14 (Scheme 4). The formation of the latter compounds 13–14 seemed to occur
through the aza-Michael 1,4-addition of the more basic exocyclic amino group of hetero-
cyclic amines to the electron deficient β-carbon of chalcone 4 followed by in situ dehydra-
tive cyclization and dehydrogenation leading to compounds 13–14. It is worthwhile to
mention that the regioselective formation of thermodynamically stable compounds 13
and 14 is also in the line with recent work published by El-Hashash et al.[35] The structures
1
13 and 14 were established on the basis of elemental analyses and spectral data (IR, H-
NMR, 13C-NMR, MS). The 1H-NMR spectrum of compound 13, taken as example, showed
the presence of three singlet signals at δ 2.62, 7.46, and 8.22 ppm assigned for the methyl,
pyrimidine, and triazole protons, in addition to the expected signals for allylamino and aryl
protons. Its 13C-NMR spectrum displayed the disappearance of a carbonyl carbon signal in
its precursor 4 and revealed the presence of 16 carbon signals which are compatible with its
molecular formula (C18H15ClN6S). The most important signals resonate at δ 18.8, 46.3,
154.3, 169.2 ppm characteristic for the carbons of methyl, methylene, triazole-C-2, and
thiazole-C-2, respectively. The mass spectrum of compound 13 showed a molecular ion
peak at m/z ¼ 382 (Mþ) which consistent with its molecular formula (C18H15ClN6S).
Compounds containing bithiazole frame with a hydrazone linker have been reported to
possess effective antimicrobial activity due to the synergistic effect of both rings.[36] In this
connection, we have synthesized thiazolyl thiosemicarbazone and studied its reactivity with
α-bromoketones and hydrazonoyl halides to obtain bithiazolyl hydrazones. Thus, treat-
ment of 3 with thiosemicarbazide in ethanol, under reflux, and in the presence of a catalytic
amount of hydrochloric acid furnished thiazolyl thiosemicarbazone 15. The structure of 15
was evidenced by IR spectrum which revealed the presence of absorption bands at 3376,
3305, 3199, 1601, 1298 cm−1 characteristic for NH2, NH, C N, and C S groups, respect-
=
=
1
ively. Its H-NMR spectrum showed two new singlet signals, exchangeable with D2O, at
δ 4.18, 10.40 ppm due to NH2 and NH protons. The 13C-NMR spectrum of 15 supported
the presence of a thiocarbonyl carbon signal at δ 178.6 ppm. Treatment of 15 with two
derivatives of phenacyl bromide in boiling ethanolic triethylamine solution afforded a sole
isolable, in each case, identified as 2-allylamino-4-methyl-5-(1-(2-(4-arylthiazol-2-yl)

SYNTHETIC COMMUNICATIONS®
7
hydrazono)ethyl)thiazoles 17 and 18 (Scheme 5). The formation of compounds 17–18 was
assumed to proceed through the SN2 substitution reaction of a bromide ion by a thiol
group with elimination of a molecule of HBr to give the non-isolable thioether intermedi-
ate 16 followed by in situ ring closure through the nucleophilic addition of the amino
group to a carbonyl group with the exclusion of a molecule of water. The structures of
the latter products were deduced from elemental analyses and spectral data. The IR
spectrum of compounds 17, as a representative example, revealed the presence of two
absorption bands at 3297 and 3210 cm−1 due to the two NH groups. Its 1H-NMR spectrum
revealed, besides the expected signals of the protons of the parent thiazole ring and phenyl
group, three new singlet signals resonate at δ 2.35, 7.39, 11.03 ppm due to the protons of
methyl group, thiazole-H5, and NH proton, respectively. Further, the 13C-NMR spectrum
of 17 exhibited sixteen carbon signals and its mass spectrum revealed a molecular ion peak
at m/z ¼ 369 (Mþ) those agrees with its molecular formula (C18H19N5S2).
Similar treatment of compound 15 with nitrilimines 20, generated in situ from the
reaction of hydrazonoyl chlorides 19[37] with triethylamine, in boiling ethanol furnished
the respective bithiazolyl hydrazones 22–24 in high yields. The formation of compounds
22–24 appeared to proceed through initial creation of the non-isolable thiohydrazonate
intermediate 21, which undergoes ring closure with elimination of a molecule of water
(Scheme 5). The structures of compounds 22–24 were inferred from their correct elemental
analyses and spectral data. The IR spectrum of compound 24, as an example, displayed
absorption bands at 3191, 3074, 1589, 1562 cm−1 assignable to two NH, C N, and N N
=
=
1
groups, respectively. Its H-NMR spectrum exhibited, besides the expected signals of the
protons of the main thiazole ring, four singlet signals at δ 2.49, 2.55, 2.56, 10.59 ppm owing
to the protons of three methyl groups, and NH proton, respectively. There is also a pair of
doublet signals resonate at δ 7.31 and 7.49 ppm due to the four protons of p-substituted
benzene ring. The 13C-NMR spectrum of 24 explored the presence of 17 carbon signals.
Scheme 5. Synthetic route of 2-allylamino-4-methyl-5-(1-(2-(thiazol-2-yl)hydrazono)ethyl)thiazoles.

8
S. BONDOCK AND A. M. FOUDA
The most relevant signals resonate at δ 16.9, 17.3, 19.6, 46.7, 168.2, 168.9, 176.7 ppm
=
assignable to the carbons of three methyl groups, NCH2, C N, thiazole-C-2, and
thiazole-C20, respectively.
Antimicrobial evaluation
All of the newly synthesized compounds were tested for their in vitro antimicrobial
activities against the human pathogenic microbes such as Streptococcus pneumoniae
(RCMB 010010), Bacillus subtilis (RCMB 010067), Staphylococcus epidermidis (RCMB
010024) as examples of Gram-positive bacteria, Escherichia coli (RCMB 010052),
Proteus vulgaris (RCMB 010085), Klebsiella pneumoniae (RCMB 010093) as examples of
Gram-negative bacteria, and Aspergillus fumigatus (RCMB 02568), Syncephalastrum
racemosum (RCMB 05922) as examples of fungal strains.
Agar-diffusion method was utilized for the initial run of antibacterial and antifungal
activities. Ampicillin, gentamycin, and amphotericin B were used as standard antibacterial
and antifungal agents. The results were recorded for each substance as the average diameter
of the inhibition zones (IZ) of bacterial or fungal growth around the disks in mm. The
minimum inhibitory concentration (MIC) measurements were noted for compounds
showed large growth inhibition zones (>12 mm) using twofold serial dilution method.[38]
The inhibition zone diameters values are ascribed to the tested initial concentrations
(5000 µg mL−1) as a starting test, and the MICs (µg mL−1) are shown in Table 1.
Antibacterial activity
The results depicted in Table 1 revealed that compounds 4, 5, 7, 15, 17, 18, 22, 23, and 24
and had wide-ranging spectrum activity against all the tested Gram-positive bacteria. The
MIC listed in brackets in Table 1, showed that the 5-(2-pyrazolin-3-yl)thiazole 5 and
bithiazolylhydrazone 24 had two-fold higher activity than ampicillin against S. pneumoniae
(MIC, 0.06 µg/ mL). 5-(1-Thiocarbamoyl-2-pyrazolin-3-yl)thiazole 7 and thiazolyl-
hydrazothiazole 18 were exhibited fourfold higher potency of ampicillin against
S. pneumoniae (MIC, 0.03 µg mL−1) and B. subtilis (MIC, 0.06 µg mL−1). Compound 7
was also showed half the potency of ampicillin against S. epidermidis (MIC, 0.12 µg mL−1).
Concerning the anti-Gram-negative bacterial activity, compounds 7, 22, and 23 were
displayed equipotent activity to gentamycin against K. pneumoniae (MIC, 0.03 µg mL−1).
Although, the thiazolyl chalcone 4 and 5-(2-pyrazolin-3-yl)thiazoles 5 and 7 revealed
higher potency than gentamycin against E. coli (MIC, 0.12–0.03 µg mL−1). Unexpectedly,
compounds 3, 6, 9, 12, and 14 were displayed no activity against P. vulgaris.
The results of antibacterial testing revealed that most of the investigated compounds
showed variable inhibitory effects on the growth of tested Gram-positive and Gram-negative
bacterial strains. In general, most of the prepared 5-hetarylthiazoles exhibited better activity
against the Gram-negative rather than Gram-positive bacterial strains. It was also noted that
transformation of thiazolyl chalcone 4 to thiazole bearing [1,2,4]triazolo[1,5-a]pyrimidine
or benzimidazo[1,2-a]pyrimidine moiety decreased the antibacterial activity.
Antifungal activity
The antifungal screening revealed that the thiazolyl chalcone 4, and 5-(2-pyrazolin-3-yl)
thiazoles 7, 8, and bithiazolyl hydrazones 17, 18, and 22 had broad spectrum antifungal

9

10
S. BONDOCK AND A. M. FOUDA
activity. Compounds 7 and 24 showed equipotent activity to amphotericin B (Table 1) against
A. fumigatus (MIC, 0.12 µg mL−1). Whereas, compounds 4 and 22 displayed twofold and four-
fold potency to amphotericin B against A. fumigatus (MIC, 0.03–0.06 µg mL−1), respectively.
Furthermore, compounds 4, 10, 14, and 15 had equipotent activity to amphotericin B
against S. racemosum (MIC, 7.81 µg mL−1). Interestingly, compounds 12 and 13, those
had weak antibacterial activity, displayed high antifungal activity in comparison to
amphotericin B.
Structure–activity relationship
In this study we examined the synergistic effect of the thiazole hybrid with chalcone,
pyrazoline, isoxazoline, pyrimidine, azolopyrimidine and/or thiazole on the different
microbes and the results revealed the following assumptions:
. Conversion of acetyl group in 3 to thiazolylchalcone 4 increased the antimicrobial activity.
. Cyclization of thiazolylchalcone with substituted hydrazines enhanced the antibacterial
activity.
. Substitution of hydrogen at position 1 of pyrazoline ring of compound 5 by a thio-
carbomyl group (–CSNH2) as in compound 7 improved the antimicrobial activity.
. Transformation of thiazolyl chalcone 4 to either [1,2,4]triazolo[1,5-a]pyrimidine 13 or
benzimidazo[1,2-a]pyrimidine 14 diminished the antibacterial activity.
. Cyclization of thiazolyl thiosemicarbazone 15 to bithiazolyl hydrazones increased the
antibacterial and antifungal activity.
. Insertion of a pharmacophoric azo group and a halogen substituent at the phenyl group
attached to a thiazole ring at position 4 enhanced the antimicrobial activity.
Conclusion
The aim of the current study was to synthesize and investigate the antimicrobial activities
of some novel 2-allylamino-4-methyl-5-hetarylthiazoles with the hope of finding new
structure that can be used as an effective antimicrobial agents. Our aim has been achieved
by the synthesis of three different groups of structure hybrids comprising basically the
thiazole core attached to 1-substituted pyrazolines, pyrazolinyl-thiazoles, isoxazoline,
pyrimidine, azolopyrimidines, or hydrazothiazole fragment. The obtained results clearly
displayed that compounds derived from pyrazolines and bithiazoles exhibited higher
antimicrobial activity than those from pyrimidine and its fused analogue structure variants.
Merging of two thiazole ring in one molecule through a hydrazone linker gives an
opportunity in medicinal chemistry to discover new potent antimicrobial agents.
Experimental
This includes general procedure for the synthesis of compounds 9–10, 17–18, and 22–24.
Experimental procedures for the intermediate and spectral data of all compounds are
presented in supporting information.
General procedure for the synthesis of 2-allylamino-4-methyl-5-(1-(2-(5-
arylazo-4-methylthiazol-2-yl)hydrazono)ethyl)thiazoles 22–24
To a solution of a compound 15 (1.35 g, 0.005 mol) and an appropriate equivalent amounts
of hydrazonoyl chlorides 19 (0.005 mol) in ethanol (30 mL), was added 0.5 mL of

SYNTHETIC COMMUNICATIONS®
11
triethylamine. The solution was heated under reflux for 2 h and then cool down to room
temperature. The resulting dyes was collected by filtration, washed with aqueous ethanol,
dried well, and recrystallized from glacial acetic acid to afford compounds 22–24.
2-Allylamino-4-methyl-5-(1-(2-(5-(4-fluorophenylazo)-4-methylthiazol-2-yl)hydrazono)
ethyl)thiazole (22)
Red crystals, yield (85%), mp 197–198 °C; IR (KBr) νmax (cm−1): 3393 (NH), 3255 (NH),
2
3
3033 (CH-sp ), 2956 (CH-sp ), 1626 (C C), 1601 (C N), 1556 (N N); 1H-NMR
(DMSO-d6): δppm ¼ 2.45 (s, 3H, CH3), 2.53 (s, 3H, CH3), 2.58 (s, 3H, CH3), 3.91 (t,
J ¼ 6.0 Hz, 2H, NCH2), 5.16–5.29 (m, 2H, CH2¼), 5.90 (m, 1H, CH¼), 7.28 (d, J ¼ 7.5 Hz,
2H, Ar-H3,5), 7.46 (d, J ¼ 7.5 Hz, 2H, Ar-H2,6), 8.31 (t, J ¼ 5.6 Hz, 1H, NH), 10.62 (s, 1H,
NH); 13C-NMR (DMSO-d6): δppm ¼ 16.4 (CH3), 17.1 (CH3), 18.8 (CH3), 46.5 (CH2N),
=
=
=
0
115.2 (thiazole-C5), 116.0 (2CHAr), 116.8 (CH2¼), 121.1 (thiazole-C5 ), 129.8 (2CHAr),
0
133.1 (CH¼), 138.6 (CAr), 148.4 (thiazole-C4), 160.1 (CAr), 162.1 (thiazole-C4 ), 167.2
þ
=
0
(C N), 169.1 (thiazole-C2), 175.1 (thiazole-C2 ); MS m/z (%): 429 (M , 25.2), 414 (16.6),
388 (37.5), 334 (29.3), 306 (100), 235 (60.2), 180 (75.4), 153 (42.9), 114 (18.5), 95 (30.8),
82 (33.7), 56 (55.8); Anal. Calcd. for C19H20FN7S2 (429.12): C, 53.13; H, 4.69; N,
22.83%. Found: C, 53.11; H, 4.63; N, 22.80%.
Funding
We express our appreciation to the Deanship of Scientific Research at King Khalid University,
Saudi Arabia for funding this work through General Research Project under grant number
(G.R.P.-145-38).
ORCID
Samir Bondock
http://orcid.org/0000-0003-1622-1599
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