Synthesis and antimicrobial activity evaluation of novel 4-thiazolidinones containing a pyrone moiety

Article abstract of DOI:10.1080/00397911.2014.970278

A series of thiosemicarbazones 3a-d and 4-thiazolidinones 5a-d, 7a-d, and 9a-h were synthesized and evaluated for their in vitro antimicrobial activity. Condensation of 3-acetyl-4-hydroxy-6-methyl-2H pyran-2-one1 (dehydroacetic acid) with thiosemicarbazide 2a-d in ethanol at room temperature yielded the thiosemicarbazones 3a-d. These compounds were exploited to synthesize the 4-thiazolidinones 5a-d via their reactions with ethyl 2-bromo propionate4. Derivatives 7a-d were prepared by reaction of the thiosemicarbazones 3a-d with phenyl bromoacetate 6. The 4-thiazolidinones 9a-h were obtained by treatment of compound 3a or 3c with maleimide derivatives 8a-d in refluxing ethanol, under sulfuric acid catalysis. All compounds were screened in vitro for their antibacterial and antifungal activities against five human pathogens microorganisms: Escherichia coli ATCC 25992, Pseudomonas aeruginosa ATCC 27852, Staphylococcus aureus ATCC 43300, Staphylococcus aureus ATCC 25923, and Candida albicans.

Full text of DOI:10.1080/00397911.2014.970278

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Synthesis and Antimicrobial Activity
Evaluation of Novel 4-Thiazolidinones
Containing a Pyrone Moiety
Rosa Nechak a , Samia Aichouche Bouzroura a , Yamina Benmalek
b , Lydia Salhi a , Sophie P. Martini c , Vincent Morizur c , Elisabet
Dunach c & Bellara Nedjar Kolli a
a Laboratory of Applied Organic Chemistry , Houari Boumediene
University of Sciences and Technology , Algiers , Algeria
b Laboratory of Microbiology , Houari Boumediene University of
Sciences and Technology , Algiers , Algeria
c Institut de Chimie de Nice UMR 7272 , Université de Nice-Sophia
Antipolis , Nice , France
Accepted author version posted online: 06 Oct 2014.Published
online: 01 Dec 2014.
To cite this article: Rosa Nechak , Samia Aichouche Bouzroura , Yamina Benmalek , Lydia Salhi ,
Sophie P. Martini , Vincent Morizur , Elisabet Dunach & Bellara Nedjar Kolli (2015) Synthesis and
Antimicrobial Activity Evaluation of Novel 4-Thiazolidinones Containing a Pyrone Moiety, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
45:2, 262-272, DOI: 10.1080/00397911.2014.970278
To link to this article: http://dx.doi.org/10.1080/00397911.2014.970278
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Synthetic Communications1, 45: 262–272, 2015
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.970278
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
EVALUATION OF NOVEL 4-THIAZOLIDINONES
CONTAINING A PYRONE MOIETY
Rosa Nechak,1 Samia Aichouche Bouzroura,1
Yamina Benmalek,2 Lydia Salhi,1 Sophie P. Martini,3
Vincent Morizur,3 Elisabet Dunach,3 and Bellara Nedjar Kolli1
1Laboratory of Applied Organic Chemistry, Houari Boumediene University
of Sciences and Technology, Algiers, Algeria
2Laboratory of Microbiology, Houari Boumediene University of Sciences and
Technology, Algiers, Algeria
3
´
Institut de Chimie de Nice UMR 7272, Universite de Nice-Sophia Antipolis,
Nice, France
GRAPHICAL ABSTRACT
Abstract A series of thiosemicarbazones 3a–d and 4-thiazolidinones 5a–d, 7a–d, and 9a–h
were synthesized and evaluated for their in vitro antimicrobial activity. Condensation of
3-acetyl-4-hydroxy-6-methyl-2H pyran-2-one1 (dehydroacetic acid) with thiosemicarba-
zide 2a–d in ethanol at room temperature yielded the thiosemicarbazones 3a–d. These com-
pounds were exploited to synthesize the 4-thiazolidinones 5a–d via their reactions with ethyl
2-bromo propionate4. Derivatives 7a–d were prepared by reaction of the thiosemicarbazones
3a–d with phenyl bromoacetate 6. The 4-thiazolidinones 9a–h were obtained by treatment of
compound 3a or 3c with maleimide derivatives 8a–d in refluxing ethanol, under sulfuric
acid catalysis. All compounds were screened in vitro for their antibacterial and antifungal
activities against five human pathogens microorganisms: Escherichia coli ATCC 25992,
Pseudomonas aeruginosa ATCC 27852, Staphylococcus aureus ATCC 43300, Staphylo-
coccus aureus ATCC 25923, and Candida albicans.
Keywords Antimicrobial activity; maleimide; 4-thiazolidinones; thiosemicarbazones
Received July 23, 2014.
Address correspondence to Bellara Nedjar Kolli, Laboratory of Applied Organic Chemistry,
Houari Boumediene University of Sciences and Technology, BP 31, El-Alia, Bab-Ezzouar, 16111,
Algiers, Algeria. E-mail: bnkollidz@gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
262

NOVEL 4-THIAZOLIDINONES
263
INTRODUCTION
In recent years, 4-thiazolidinones and their derivatives have become among the
most extensively investigated compounds. They constitute an important group of
heterocyclic compounds, displaying a broad spectrum of biological activity.[1–3] They
have found uses, for example, as antimicrobial[4–6] and anti-inflammatory drugs[7–9]
and anti-HIV derivatives.[10–12]
The thiazolidinone ring system belongs to the privileged structure in modern
medicinal chemistry, particularly in discovery of new antitumor and anti-angiogenic
agents.
A literature survey revealed that many different protocols have been developed
in a way that allows the synthesis of 4-thiazolidinone skeletons, and several reactants
or heterocyclic compounds have been employed for the preparation of 4-thiazolidi-
none moiety.[13,14] The main synthesis routes to 4-thiazolidinones involve three
components (an aldehyde, an amine or thiosemicarbazide, and mercaptoacetic acid
or halogenoester), either in one- or two-step processes.[15–20]
We report in this article the syntheses of a new class of structurally novel
4-thiazolidinone derivatives, incorporating two known bioactive heterocyclic nuclei
such as pyrone and 4-thiazolidinone, known to be active towards (Gþ and G-) and
yeast. Pyrones and their fused derivatives have attracted a great deal of interest
because of their wide range of biological activities.[21–23] The incorporation of another
heterocyclic moiety in pyrone either in the form of a substituent or as a fused compo-
nent often leads to incredible diverse biological activity.
In this study, new 4-thiazolidinones 5a–d, 7a–d, and 9a–h were synthesized
starting from commercially dehydroacetic acid, which possesses three active sites in
positions 2, 3, and 4 corresponding to ester, acetyl, and hydroxyl groups respectively
for nucleophilic substitution by amine. It has been reported that the carbonyl of acetyl
group in position 3 in dehydroacetic acid proved to be the more reactive site toward
coupling reaction with nucleophilic reagents.[24] In this context, we prepared thiose-
micarbazones 3, via treatment of dehydroacetic acid with thiosemicarbazides 2, to
investigate its reactivity toward some electrophilic reagents. All synthesized com-
pounds were tested for their in vitro antimicrobial properties against Gram-positive,
Gram-negative, and antifungal bacteria.
RESULTS AND DISCUSSION
Chemistry
In continuation of our ongoing work aiming at the development of efficient
methods for the synthesis of heterocyclic compounds,[25] we carried out an efficient
preparation of 4-thiazolidinones derivatives 5a–d and 7a–d (Scheme 1). We also
report a new synthetic route to the formation of 4-thiazolidinone compounds
9a–h, from reaction of the precursors 3a or 3c and maleimide derivatives 8a–h in
refluxing ethanol.
In our study, we initially isolated the thiosemicarbazones intermediates 3a–d
in quantitative yields (81–91%) after stirring the thiosemicarbazides 2a–d with
dehydroacetic acid 1 in ethanol at room temperature.

264
R. NECHAK ET AL.
Scheme 1. Synthetic pathway to generate 4-thiazolidinone derivatives 5 and 7. Reagents and conditions:
(i) rt, EtOH; (ii) ethyl 2-bromopropionate 4, 3 equiv CH3COONa anhydrous, conc. H2SO4 or 0.12%
of keggin heteropolyacid (H3PW12O40, nH2O), CH3CN, reflux; (iii) phenyl bromoacetate 6, 3 equiv
CH3COONa anhydrous, conc. H2SO4, CH3CN, reflux.
Spectral 1H NMR data of thiosemicarbazones 3a–d indicated that these
compounds exist as a tautomeric equilibrium between the enol (I) and the ketone
(II) forms in an average ratio of 1:2, represented in Scheme 2.
For example, concerning 3a, the chemical shift of the singlet corresponding to
methyl protons of the pyrone unit was observed at d: 2.12 ppm in form (I) and at
d: 2.16 ppm in form (II). The methylene proton (CH) appeared as a singlet at d:
5.93 ppm (I) and at d: 6 ppm in form (II). Methyl imine protons resonated at d:
2.4 ppm in form (I) and at d: 2.03 ppm in form (II). The 13C NMR spectrum exhibited
=
a signal at 184 ppm assigned to the C S bond. The infrared (IR) spectra showed
=
bands around 1150–1156 cmꢀ1 and 1575 cmꢀ1 assigned to C S and C N bending
vibrations, from the thiosemicarbazone fragment.
=
Subsequently, 4-thiazolidinone compounds 5a–d were synthesized in good
yields as described in Table 1, by reaction of the intermediates 3a–d, ethyl 2-bromo
propionate 4, and 3 equiv of sodium acetate anhydrous in the presence of two
drops of concentrated sulfuric acid or 0.12 mol% of keggin heteropolyacid[26,27]
(H3PW12O4, n H2O) in refluxing acetonitrile (Scheme 1).
As shown in Table 1, compounds 5a–d were formed efficiently when we used
H3PW12O4, n H2O as catalyst comparatively with sulfuric acid use. The reaction times
were shortened from 2 h to 30 min for derivatives 5a–b, 1 h to 15 min for compound
5c, and 30 to 5 min for 5d. However, the reaction yields are slightly lower compared
with sulfuric acid use.
Scheme 2. Thiosemicarbazones 3 tautomesism.

NOVEL 4-THIAZOLIDINONES
265
Table 1. Yields and reaction times of compounds 3a–d, 5a–d, and 7a–d
Entry
Compound
Yield (%)
Time (min)
1
77a (72)b
120a (30)b
2
3
4
5
6
86a (80)b
88a (84)b
90a (88)b
88
120a (30)b
60a (15)b
30a (5)b
20
91
20
7
8
80
78
10
20
aReaction using concentrated sulfuric acid.
bReaction using heteropolyacid H3PW12O40, nH2O.
To improve our studies, we applied the same methodology to synthesize 4-
thiazolidinones 7a–d from compounds 3a–d and phenyl bromoacetate 6. The pro-
ducts 7a–d were isolated in excellent yields as shown in Table 1.
The appearance of the double signal at 1.53 (J ¼ 7 Hz) ppm due to –CH3 and
the quadruplet signal at 4.43 ppm (J ¼ 7 Hz, J ¼ 14 Hz) attributed to –CH in
1H NMR confirms the formation of 4-thiazolidinones 5a–d. The IR spectra of
4-thiazolidinone showed absorption bands at 1711–1718 and 1313–1357 cmꢀ1 corre-
=
=
sponding to the C O and the N C-S groups of thiazolidinone ring. Moreover, in the
13C NMR spectrum, signals at 17.4, 43, and 178 ppm were assigned to CH3, CH, and
=
C O (thiazolidinone) carbons.
1
The signal of methylene (CH2) which appeared at 4.5 ppm in H NMR and at
34 ppm in 13C NMR corroborates the structures 7a–d.
The proposed mechanism of formation of 4-thiazolidinones 5 or 7 is illustrated
in Scheme 3.

266
R. NECHAK ET AL.
Scheme 3. Mechanistic pathway proposed for the synthesis of compounds 5.
The formation of 5 or 7 was assumed to proceed through a nucleophilic attack of
the sulfur atom of the thiosemicarbazones 3 onto the bromoester, followed by the intra-
molecular cyclization with elimination of ethanol and regeneration of sulfuric acid.
We also described a simple new strategy of the preparation of thiazolidinones
9. The reaction of 1 equiv of the key intermediates 3a or 3c with the appropriate
maleimide 8a–h in the presence of two drops of concentrated sulfuric acid in
refluxing ethanol for 3 to 4 h afforded structures 9a–h in moderate yield (46–52%).
The solid was obtained after purification by column chromatography (eluent: ethyle
acetate) or by recrystallization in acetonitrile as represented in Scheme 4.
The formation of compounds 9a–h results from initial attack of the sulfur atom
of thiosemicarbazone group on the double bond of maleimide followed an intermedi-
ate A (not isolated). The ring opening of maleimide is obtained by nucleophic attack
of nitrogen azote NR on the functional carbonyl, affording thiazolidinone structures
9a–h (Scheme 5).
For example, in IR spectra, the formation of compound 9a was confirmed
through the presence of absorption bands around 1341 and 1704 cmꢀ1 attributed
=
to N C-S-C N and C O bending vibrations. Consequently, the absence of the
=
=
13
signal at 184 ppm in C NMR spectra, attributed to C S, was also a parameter
=
1
considered for the confirmation of the cyclization reaction. The H NMR spectra
Scheme 4. Synthetic pathway to generate 4-thiazolidinone structures 9a–h.

NOVEL 4-THIAZOLIDINONES
267
Scheme 5. Plausible mechanism for the formation of 4-thiazolidinones 9.
exhibited signals at 2.77 ppm (3J ¼ 9 Hz, 2J ¼ 17 Hz), 3.07 ppm (3J ¼ 4 Hz,
2J ¼ 17 Hz), and 4.58 ppm (3J ¼ 4 Hz and 9 Hz), assigned to the Ha, Hb, and Hx
appearing as double doublet (ABX pattern), due to interaction with nonequivalent
methylene protons Ha and Hb with Hx proton. The signals observed at 7.09–
7.58 ppm assigned to the nonequivalent amine protons were also compatible with
the ring opening of the maleimide unit.
Antimicrobial Evaluation
Antibacterial activity of all compounds was determined by the well diffusion
method[28] and the diameter of inhibition zone was measured as indicated by Nataraja
et al.[29] and Vinod et al.[30] Antimicrobial activity of the synthesized products 3a–d,
5a–d, 7a–d, and 9a–h was evaluated against five microorganisms, known to cause
some infections in humans: Escherichia coli ATCC 25992, Pseudomonas aeruginosa
ATCC 27852, Staphylococcus aureus ATCC 43300, Staphylococcus aureus ATCC
25923, and Candida albicans. The results obtained (Table 2) revealed that compounds
3a, 3b, 7c, and 9a–h (except 9f) showed bactericidal activity toward Gram-positive
bacteria Staphylococcus aureus ATCC43300. Compounds 7a–d (except 7b) demon-
strated the greatest inhibition activity against Staphylococcus aureus ATCC 25923.
All the tested compounds, 3b–d, 5a–d, 7c, 7d, and 9a–e (except 9d) are distinguished
by a strong inhibitory activity on the growth of the Gram-negative bacteria
Pseudomonas aeruginosa ATCC 27852. Compounds 3a–d (except 3c) and 7d are the
most active against Candida albicans. Very low inhibitory activity on the growth of
Escherichia coli ATCC 25992 is observed for compounds 3a, 5a, 7c, and 9a, c. As
shown in Table 2, some compounds did not show any activity toward Gram-positive
bacteria, Gram-negative bacteria, and Candida albicans.

268
R. NECHAK ET AL.
Table 2. Antimicrobial activity of synthesized compounds (diameter zones in mm)
Gram-positive bacteria
Gram-negative bacteria
Fungi
Candida
albicans
Staphylococcus
aureus
(ATCC-43300)
Staphylococcus
aureus
Escherichia
coli
Pseudomonas
aeruginosa
Compound
(ATCC-25923) (ATCC-25992) (ATCC-27852) (ATCC-43300)
3a
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
7d
9a
9b
9c
9d
9e
9f
Bactericidal activity
Bactericidal activity
—
—
—
—
—
—
—
—
20
—
28
22
—
—
—
—
—
—
—
—
12
—
—
—
—
—
—
—
—
—
13
—
14
—
15
10
—
—
—
10
—
20
17
20
—
—
—
—
—
—
25
13
15
10
18
—
25
—
—
—
20
18
—
18
—
—
—
—
—
14
—
22
—
12
—
—
—
14
—
—
—
—
—
—
—
—
—
17
Bactericidal activity
26
Bactericidal activity
Bactericidal activity
Bactericidal activity
Bactericidal activity
Bactericidal activity
15
9g
9h
Bactericidal activity
Bactericidal activity
Many synthetic compounds feature activity against microorganisms. The inhibi-
tory activity increases in the compounds having substitution.[31,32] However, it is
reported that these compounds show a variety of pharmacological properties such as
antibacterial, antifungal, and biological activities.[33,34] The results obtained in this study
indicate that the attachment of hydrogen, methyl, or amid groups at the 5-position of
4-thiazolidinone moiety gained the different activities of all expected compounds 3.
From the structure–activity relationship it is clear that substituted compounds
0
=
=
=
3b (R CH3), 7c (R C2H5), and 9e (R H, R ¼ H) have the broad spectrum of
antibacterial activity against the Gram-positive bacteria (S. aureus) and Gram-
=
negative bacteria (P. aeruginosa). The compound 7d (R C6H5) has the very broad
spectrum of antibacterial and antifungal activity. The inhibitory activity can prevent
function of some important molecules such as extracellular and intracellular enzymes
and microbial metabolism. Following this activity, the synthesis of peptidoglycan in
the cell wall as well as the synthesis of DNA and RNA, proteins and other important
molecules can be inhibited.[35–37]
EXPERIMENTAL
1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethan-1-one N-Ethyl
Thiosemicarbazone (3c)
A solution of 0.01 mol (1.68 g) of dehydroacetic acid 1 and 0.01 mol of ethyl
thiosemicarbazide 2c in 20 mL of EtOH was stirred for 2 h at room temperature.

NOVEL 4-THIAZOLIDINONES
269
The precipitate obtained was filtered aꢀn1d washed with ethanol. White solid, yield
90%, mp 170–171 ꢁC. IR (KBr, n= cm ): 3257 (O-H), 3118 (N-H), 1718 (C O),
=
1
3
=
=
1575 (C N), 1150 (C S). H NMR (200 MHz, DMSO-d6): d 1.08 (t, 3H, JHH
7 Hz, CH2CH3 (I, II)), 2.12 (s, 3H, CH3(I)), 2.04 (s, CH3(II)), 2.39 (s, 3H,
¼
3
NCCH3(I)), 2.18 (s, NCCH3(II)), 2.48 (q, 2H, JHH¼s 7 Hz, CH2(I, II)), 5.92 (s,
3
1H, CH(I)), 6.04 (s, CH(II)), 8.28 (t, 1H, JHH¼ 7 Hz, NHCH2(I, II)); 9.43 (s, 1H,
NH(I)), 10.38 (s, NH(II)). 13C NMR (50 MHz, DMSO-d6): d14 (CH3CH2), 16.5
(NCCH3), 19.3 (CH3pyr), 39.4 (CH2), 96.2 (C¼COH), 104.2 (CH), 163.1 (N¼CCH3),
=
=
163.4 (C¼C-O), 167 (C Opyr), 176.8 (COH), 179.9 (C S). MS m=z (%) ¼ 269
(Mþ., 41), 166 (100), 138 (15), 151 (25), 125 (22), 43(53). HRMS m=z calcd. for
C11H16N3O3S [M þH)þ: 270.32010. Found: 270.32012.
General Procedure for the Synthesis of 4-Thiazolidinones (5a–d)
Thiosemicarbazones 3a–d (0.01 mol) and 0.02 mol of ethyl 2-bromopropionate
4 were refluxed in 30 mL of acetonitrile in the presence of 0.03 mol (0.246 g) of anhy-
drous NaOAc and two drops of concentrated sulfuric acid for 1 to 3 h. The solid
formed was recuperated by filtration and recrystallized in acetonitrile (method A).
2-f[1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene]
hydrazinylideneg-5-methyl-1,3-thiazolidin-4-one (5a)
ꢀ1
Yellow solid, yield 77%, mp 205 ꢁC. IR (KBr, n=cm ): 3443 (O-H), 1612 (C O
=
1
=
pyr), 1711 (C O thiaz), 1349 (NCS). H NMR (200 MHz, DMSO-d6): d 1.53 (d, 3H,
3
=
JHH ¼ 7 Hz, CH3thiaz), 2.14 (s, 3H, CH3pyr), 2.61 (s, 3H, CH3-C N), 4.43 (q, 1H,
3JHH¼ 7 Hz, CHthiaz), 5.96 (s, 1H, CHpyr), 2.19 (s, 1H, NH). 13C NMR (50 MHz,
DMSO-d6): d 16.5 (CH3thiaz), 18.4 (CH3CN), 19 (CH3pyr), 44 (CHthiaz), 94.8
(C¼COH), 104 (CHpyr), 158.4 (C-Opyr), 162 (H3C-C¼N), 163.1 (N¼CS), 168.8
(C Opyr), 175.9 (COH), 179.9 (C Othia). MS m=z (%) ¼ 295 (Mþ., 5), 166 (30), 138
(100), 129 (24), 101 (42). HRMS m=z calcd. for C12H14N3O4S [M þ H]þ:
296.06995. Found: 296.06992.
=
=
General Procedure for Synthesis of Compounds 7a–d
Thiosemicarbazones (0.01 mol) 3a–d and 0.02 mol of phenyl bromoacetate
6 were refluxed in 30 mL of acetonitrile in the presence of 0.03 mol (0.246 g) of
anhydrous NaOAc and two drops of concentrated sulfuric acid for 1 to 3 h. The solid
formed was recuperated by filtration and recrystallized in acetonitrile.
2-f2-[1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)ethylidene]
hydrazinylg-1,3-thiazolidin-4-one (7a)
ꢀ1
White solid, yield 88%, mp 210 ꢁC. IR (KBr, n=cm ): 3414 (O-H), 1614 (C O
=
1
=
pyr), 1704 (C O thiaz), 1258 (NCS). H NMR (200 MHz, DMSO-d6): d 2.13 (s, 3H,
=
CH3pyr), 2.59 (s, 3H, CH3-C N), 4.43 (s, 2H, CH2), 5.96 (s, 1H, CHpyr), 12.2 (s, 1H,
NH). 13C NMR (50 MHz, DMSO-d6): d 16.7 (CH3CN), 19.3 (CH3pyr), 34.5 (CH2),
95 (C¼COH), 104.2 (CHpyr), 160 (C-O), 161.8 (CCH3 ¼ N), 163.8 (N¼CS), 168.5

270
R. NECHAK ET AL.
(C Opyr), 173.1 (C-OH), 180 (C Othia). MS m=z (%) ¼ 281 (Mþ., 7), 166 (58), 138
(100), 115 (30). HRMS m=z calcd. for C11H12N3O4S [M þ H]þ: 282.28774. Found:
282.28771.
=
=
General Method for the Synthesis of Compounds 9a–h
A mixture of thiosemicarbazones 3a or 3c (0.01 mol), appropriate maleimide
8a–d (0.01 mol), and two drops of concentrated sulfuric acid (12 N) in 30 mL of
acetonitrile was refluxed for 3–4 h. The reaction mixture was then cooled at
room temperature and the solid precipitated was filtered, abundantly washed with
acetonitrile and ethanol, and then recrystallized, or the precipitate was purified by
column chromatography using ethyl acetate as eluent.
2-(3-Ethyl-2-f2-[1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)
ethylidene]hydrazinylg-4-oxo-1,3-thiazolidin-5-yl)acetamide (9a)
White solid, yield 48%, mp 255–256 ꢁC. IR (KBr, n=cmꢀ1): 3397 (O-H), 3298;
=
=
=
3179 (NH2), 1673 (C O pyr), 1704 (C O thiaz), 1583 (NC O), 1344 (NCS).
3
1H NMR (200 MHz, DMSO-d6): d 1.18 (t, 3H, JHH ¼ 7 Hz, CH3CH2), 2.17 (s, 3H,
3
2
=
CH3pyr), 2.68 (s, 3H, N CCH3), 2.77 (dd, Ha, JHH ¼ 9 Hz, JHH¼ 17 Hz), 3.07
3
2
3
(dd, Hb, JHH¼ 4 Hz, JHH ¼ 17 Hz), 3.75 (q, 2H, JHH ¼ 7 Hz, CH2), 4.58 (dd, Hx,
3JHH¼ 4 Hz and 9 Hz), 5.98 (s, 1H, CHpyr), 7.09, 7.58 (s, 2H, NH2).13C NMR
=
(50 MHz, DMSO-d6): d 11.4 (CH3CH2), 17.1 (N CCH3), 19.5 (CH3pyr), 37.2
(CH2CH3), 38.2 (CH2CONH2), 47.2 (CHthiaz), 94.5 (HOC¼C), 104.1 (CHpyr),
=
=
159.2 (N CCH3), 162.2 (CCH3), 163.4 (C Opyr), 169.2 (N¼CS), 170 (COH), 173
(CONH2), 180.1 (C Othia). MS m=z (%) ¼ 366 (Mþ., 12), 308 (36), 166 (100), 151
=
(50), 58 (37). HRMS m=z calcd. for C15H19N4O5S [MþH]þ: 367.10707. Found:
367.10690.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra, and results of antimicrobial
activity for this article can be accessed on the publisher’s website.
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