Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in indole series

Article abstract of DOI:10.1007/s00706-021-02823-6

Abstract: New thiosemicarbazones were synthesized in excellent yield reaction of indole derivatives with thiosemicarbazides. These thiosemicarbazones were reacted with ethyl bromoacetate to produce original heterocyclic-substituted indole derivatives possessing a 4-oxo-thiazolidine group. Analytical IR and NMR spectra and elemental analysis were performed to reveal their structures. The antimicrobial activity of all synthesized compounds was evaluated for antibacterial activity in vitro against Gram-positive and Gram-negative bacteria. Antibacterial screening data showed that two compounds demonstrated activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. These preliminary results indicate that some of these newly synthesized compounds show a promising antibacterial potency. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-021-02823-6

Monatshefte für Chemie - Chemical Monthly (2021) 152:977–986
https://doi.org/10.1007/s00706-021-02823-6
ORIGINAL PAPER
Synthesis and antimicrobial activities of new thiosemicarbazones
and thiazolidinones in indole series
Abdelmadjid Benmohammed1 · Nawel Rekiba4 · Yassine Sehanine · Ahmed Amine Louail · Omar Khoumeri ·
,2,4
2,3
3
3
4
2
2
4
Mokhtaria Kadiri · Ayada Djafri · Thierry Terme · Patrice Vanelle
Received: 5 May 2021 / Accepted: 5 July 2021 / Published online: 9 August 2021
©
Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
New thiosemicarbazones were synthesized in excellent yield reaction of indole derivatives with thiosemicarbazides. These
thiosemicarbazones were reacted with ethyl bromoacetate to produce original heterocyclic-substituted indole derivatives
possessing a 4-oxo-thiazolidine group. Analytical IR and NMR spectra and elemental analysis were performed to reveal
their structures. The antimicrobial activity of all synthesized compounds was evaluated for antibacterial activity in vitro
against Gram-positive and Gram-negative bacteria. Antibacterial screening data showed that two compounds demonstrated
activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. These preliminary results indicate
that some of these newly synthesized compounds show a promising antibacterial potency.
Graphic abstract
Keywords Indoles · Thiosemicarbazones · Thiazolidinones · Nucleophilic addition · Heterocycles · Antibacterial activity
Introduction
Indoles and several N-substituted indoles are an important
class of heterocycles. These compounds have been attract-
*
*
Abdelmadjid Benmohammed
ing attention for their wide range of biological activities and
their potential in synthetic chemistry. Indole derivatives pos-
sess a broad spectrum of pharmacological activities such as
antimicrobial [1], analgesic [2], anticonvulsant [3], antiviral
abdelmadjid.benmohamed@univ-mascara.dz
Patrice Vanelle
patrice.vanelle@univ-amu.fr
[
[
4], antihypertensive [5], anti-asthmatic [6], antidepressant
7], anti-Alzheimer [8], antimalaria [9], antidiabetic [10],
1
2
Department of Chemistry, Faculty of Exact Sciences,
University of Mascara, Mascara, Algeria
and anti-HIV activities [11]. They oꢀer particular promise
in the search for new antitumor agents [12, 13]. Thiosemi-
carbazones represent a broad family of molecules with var-
ious pharmacological properties, including antiviral [14],
antibacterial [15], and antitumor activities [16]. Moreover,
thiazolidinone derivatives possess potential biological and
medicinal activities [17], among them antimycobacterial
[18], antioxidant [19], anticancer [20, 21], anticonvulsant
Laboratoire de Synthèse Organique Appliquée (LSOA),
Département de Chimie, Faculté Des Sciences Exactes Et
Appliquées, Université Oran1 Ahmed Ben Bella, BP 1524 El
M’naouer, Oran, Algérie
3
4
Unité de Microbiologie, Laboratoire Centrale, Hôpital
Militaire Régional Universitaire D’Oran Dr Amir Mohamed
Benaissa, B.P 35 Ahmed Medeghri, Oran, Algérie
Aix Marseille Université, CNRS, ICR Institut de Chimie
Radicalaire, UMR 7273, Laboratoire de PharmacoChimie
Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean
Moulin–CS 30064, 13385 Marseille Cedex 05, France
[
22], anti-inꢁammatory [23], analgesic [24], and antimi-
crobial [25–28]. In antibacterial activities, thiazolidinones
Vol.:(0
1
123456789)
3

978
A. Benmohammed et al.
are more active on Gram-negative bacteria than on Gram-
positive bacteria. In an attempt to design and synthesize new
antimicrobial molecules [29–32], we report here a synthesis
of new thiosemicarbazone and thiazolidinone derivatives
containing the indole moiety, with the aim of obtaining new
biologically active compounds. The drug design process is
based on the synthesis combining two potential pharmaco-
phore systems in one molecule.
Table 1 Preparation of thiosemicarbazone derivatives 7a–7j from
reaction between 3a, 3b and 6a–6e
Product
R1
R2
Yield/%a
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
H
3-Cl
4-F
3-CF3
2-CN
H
3-Cl
4-F
H
H
H
H
94
87
95
86
90
95
95
91
92
95
H
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
g
h
i
Results and discussion
3-CF3
2-CN
4
The starting materials, N -substituted thiosemicarbazide
j
derivatives 3a, 3b, were prepared through the nucleophilic
addition reaction of 85% hydrazine hydrate with aryl iso-
thiocyanate 1a, 1b in ethanol at room temperature [33]
a
All yields refer to chromatographically isolated pure products and
4
are relative to the respective N -substituted thiosemicarbazides 3a, 3b
(
Scheme 1). On the other hand, substituted N-benzylin-
dole-3-carboxaldehyde derivatives 6a–6e were obtained
in 90–95% yield using procedures described in the litera-
ture [34]. The appropriate commercially available indole-
thiosemicarbazones 7a–7j were conꢂrmed by the absence
−
1
of absorption in the 2500–2600 cm region [35, 36].
1
3
-carboxaldehyde (4) was treated with various substituted
The most characteristic signals in the H NMR spectrum
benzyl halides 5a–5e in the presence of K CO in N,N-
of this family of thiosemicarbazones were those correspond-
2
3
1
dimethylformamide (DMF) (Scheme 1).
ing to the –CH=N and N–H protons. H NMR analysis
Thiosemicarbazone derivatives 7a–7j were obtained
in good yields (86–95%), via condensation of substituted
N-benzylindole-3-carboxaldehyde derivatives 6a–6e with
showed the CH=N protons to be in the 8.02–8.15 ppm range,
whereas the thiourea N–H protons were found to be in the
9.50–11.63 ppm interval for N–H adjacent to the mono-sub-
stituted phenyl ring and for the N–H adjacent to the CH=N
4
N -substituted thiosemicarbazides 3a, 3b in the presence of
1
3
a catalytic amount of AcOH in ethanol at 90 °C as solvent,
as shown in Scheme 1 and Table 1.
moiety, respectively. In the C NMR spectra, the chemical
shift of the azomethine group (H–C=N) appeared at region
140.77–141.14 ppm, while for the C=S group, it occurred
in the range 175–175.65 ppm, both comparable to the lit-
erature [37, 38]. All the thiosemicarbazone compounds syn-
After recrystallization of all thiosemicarbazones 7a–7j,
1
13
they were analyzed by H and C NMR, IR, as well as
by elemental analysis. The IR spectra of compounds
1
7
a–7j showed characteristic absorptions in the range of
thesized were in conꢂguration E, as conꢂrmed by H NMR
−
1
−1
3
343–3124 cm (N–H bond), 1278–1189 cm (C=S),
spectroscopy, where a single peak was detected, indicating
a chemical shift of 8.02–8.15 ppm for hydrogen azomethine
(H–C=N–) simple [39]. In addition, a single thin-layer spot
−
1
and 1537–1550 cm (CH=N bond). Thus, the pres-
ence and predominance of the thione form of synthesized
Scheme 1
1
3

Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in…
979
was observed under chromatography (TLC), indicating the
presence of a single isomeric form. It has been noted by a
number of authors that compounds possessing a Z isomer
generally exhibit an NH-3 signal in the 14–15 ppm range,
whereas those compounds possessing an E form display a
signal in the 9–12 ppm range [40].
Table 2 Preparation of thiazolidinone derivatives 9a–9j
R1
R2
Yield/%a
Product
9
9
9
9
9
9
9
9
9
9
a
b
c
d
e
f
H
3-Cl
4-F
3-CF3
2-CN
H
3-Cl
4-F
3-CF3
2-CN
H
H
H
H
H
94
87
91
86
82
90
91
95
92
83
The reaction between ethyl bromoacetate 8 and thiosemi-
carbazone derivatives 7a–7j in absolute ethanol containing
anhydrous sodium acetate aꢀorded the corresponding 4-thia-
zolidinone compounds 9a–9j in good yields (82–95%), as
shown in Scheme 2 and Table 2.
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
g
h
i
The chemical structures of thiazolidinones 9a–9j were
1
13
j
conꢂrmed by their IR, H NMR, and C NMR spectra.
The IR spectra of the thiazolidin-4-ones showed absorp-
tion bands due to the (NCS), (C=O) groups in the regions
a
All yields refer to chromatographically isolated pure products and
are relative to the respective thiosemicarbazones 7a–7j
−
1
1
364–1328 and 1724–1711 cm , respectively.
1
Further support was obtained from the H NMR spectra,
which showed no signs of the 4-phenyl-3-thiosemicarbazone
conventional agar dilution method [41]. Minimum inhibi-
tory concentrations (MIC) are deꢂned as the concentra-
tion of a compound that inhibits the growth of the tested
microorganisms.
1
(
NH) protons. On the other hand, the H NMR spectra exhib-
ited resonances assigned to the SCH group of the thiazo-
2
lidine ring appearing as a singlet at 4.08–4.11 ppm due to
the methylene protons. The CH=N protons in these struc-
tures were observed in the 8.45–8.84 ppm region. Similarly,
3
The MIC varied from 0.25 to 128 μg/cm according to the
tested compound, compared with the standard ceftazidime
1
3
3
3
in the C NMR spectra, the chemical shift of the carbon
of the carbonyl group of 4-thiazolidinone ring occurred
between 172.30 and 172.52 ppm next to signals in the
(MIC = 0.5–4 μg/cm ), imipenem (MIC = 0.5–1 μg/cm ),
3
and gentamicin (MIC=0.06–2 μg/cm ). It has been shown
that each compound exhibited diꢀerent action. According
1
2
4
8.32–50.01 ppm region attributed to methylene groups. The
to Table 3, the product 7g (R =3-Cl, R =4-OCH ) and 9a
3
1 2
formation of thiazolidinones 9a–9j occurred in two steps.
The ꢂrst step of this reaction is thought to be S-alkylation of
thiosemicarbazide in its thiol form. The second step involved
loss of ethanol to give the thiazolidin-4-ones as shown in
Scheme 3.
(R = H, R = H) presented the best antimicrobial activity
1
2
for the three strains followed by 7h (R =4-F, R =4-OCH )
3
which exhibited a positive action against the Gram-negative
bacteria (E. coli and P. aeruginosa). Among the other syn-
1
2
1
thesized derivatives, for 7c (R =4-F, R =H), 7j (R =2-CN,
2
1
2
Previous studies have shown that thiazolidinones with
C-2- and N-3-substituted positions possess varying degrees
of inhibition against many pathogens [17]. We are therefore
considering a preliminary study of the antibacterial activ-
ity for thiosemicarbazone intermediates and thiazolidinone
targets. The antibacterial activity in vitro of the synthesized
thiosemicarbazone 7a–7j and thiazolidinone 9a–9j deriva-
tives was evaluated against a Gram-positive bacterial strain,
Staphylococcus aureus (ATCC-25923), and two Gram-
negative bacterial strains, Escherichia coli (ATCC-25922)
and Pseudomonas aeruginosa (ATCC-27853), using the
R =4-OCH ), and 9i (R =3-CF , R =4-OCH ), the activ-
3
3
3
ity toward P. aeruginosa is to be underlined with an activ-
ity higher (at least four times) than that of the reference
products.
In terms of structure–activity relationships, it can been
seen that for the thiosemicarbazones active against P. aerug-
inosa, the most active derivatives (7g, 7h, 7j) are substituted
1
in R by an electron-withdrawing group (3-Cl, 4-F, 2-CN)
2
and R by an electron-donating group (4-OCH ). Regarding
3
the possible mechanism of thiosemicarbazones, we suggest
membrane perturbing as well as intracellular mode of action
Scheme 2
1
3

980
A. Benmohammed et al.
Scheme 3
of this class of compounds, as proposed recently [42]. For
thiazolidinones, the substitution seems unfavorable, since
−
3
Table 3 Minimum inhibitory concentration (MIC/μg cm ) of the
tested compounds against Gram-negative and Gram-positive microor-
ganisms
1
2
the unsubstituted derivative 9a (R = R = H) is the most
active for the three strains.
Product
Gram−
Gram+
Escherichia coli
ATCC-25922
Pseudomonas
aeruginosa
ATCC-27853
Staphy-
lococcus
aureus
Conclusion
ATCC29523
In this study, a series of hybrid molecules indole-thiazolidi-
nones easily was synthesized in very good yields (82–95%).
The synthesized indole-thiazolidinones and their precursor
thiosemicarbazones showed good activity in antibacterial
7
7
7
7
7
7
7
7
7
7
9
9
9
9
9
9
9
9
9
9
a
b
c
d
e
f
0.25
1
>128
>128
>128
>128
>128
>128
0.25
>128
>128
>128
0.25
>128
>128
>128
0.25
>128
0.25
>128
>128
>128
>128
>128
0.25
0.25
64
>128
0.25
>128
32
>128
>128
>128
0.25
>128
>128
>128
0.5
>128
0.25
>128
>128
>128
0.25
0.25
64
0.25
0.25
>128
>128
>128
>128
>128
>128
>128
0.25
8
1
2
assays. The products 7g (R = 3-Cl, R = 4-OCH ) and 9a
3
1
2
(
R =H, R =H) showed the best antimicrobial activity for
3
the three strains tested with an MIC value 0.25 μg/cm ,
1
2
g
h
i
followed by 7 h (R = 4-F, R = 4-OCH ) which exhib-
3
ited a positive action against Gram-negative bacteria (E.
3
coli and P. aeruginosa) with an MIC value 0.25 μg/cm .
1
j
Among the other synthesized derivatives, for 7c (R =4-F,
2
1
2
1
a
b
c
d
e
f
R =H), 7j (R =2-CN, R =4-OCH ), and 9i (R =3-CF ,
3
3
2
R = 4-OCH ), the activity toward P. aeruginosa is to be
3
underlined with an activity higher (at least four times) than
that of the reference products. These results are comparable
or more potent regarding their activity than the reference
drugs. The ꢂrst structure–activity relationship conclusions
show that for thiosemicarbazones active against P. aerugi-
nosa, the most active derivatives (7g, 7h, 7j) are substituted
g
h
i
>128
>128
>128
4
0.5
0.06
1
in R by an electron-withdrawing group (3-Cl, 4-F, 2-CN)
2
j
and R by an electron-donating group (4-OCH ). For thia-
3
Ceftazidime
Imipenem
Gentamicine
1
1
2
zolidinones, the substitution seems unfavorable, since the
1
2
1
0.25
unsubstituted derivative 9a (R =R =H) is the most active.
The pharmacomodulation of these series to conꢂrm and
1
3

Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in…
981
1
3
complete their structure–activity relationship is currently
under investigation. In addition, the most active products 9a
and 7g will be tested on resistant strains in the near future.
The potential interactions of lead compounds will be studied
by means of docking for example.
3H, Ar–H), 5.58 (s, 2H, CH ) ppm; C NMR (DMSO-d ):
2
6
δ = 184.79 (C=O), 141.00 (C), 139.28 (CH), 136.44 (C),
133.30 (C), 130.66 (CH), 127.80 (CH), 127.23 (CH), 126.02
(CH), 124.75 (CH), 123.74 (CH), 122.66 (CH), 121.12 (C),
117.51 (C), 111.31 (CH), 49.06 (CH ) ppm.
2
1
‑(4‑Fluorobenzyl)‑1H‑indole‑3‑carbaldehyde (6c,
Experimental
C H FNO) Yield: 94%; white solid; m.p.: 117.1–117.7 °C;
1
6 12
1
H NMR (DMSO-d ): δ = 10 (s, 1H, CHO), 8.51 (s, 1H,
6
Melting points were determined on a Büchi B-540 apparatus
and are uncorrected. IR spectra were taken on Perkin-Elmer
Spectrum two FT-IR spectrometer and the wave numbers
indole H-2), 8.16–8.13 (m, 1H, Ar–H), 7.66–7.62 (m,
1H, Ar–H), 7.45–7.39 (m, 2H, Ar–H), 7.35–7.27 (m, 2H,
Ar–H), 7.21 (t, 2H, J=8.85 Hz, Ar–H), 5.56 (s, 2H, CH )
2
−
1
13
reported in cm . Elemental analyses were carried out at
the Spectropole; Faculté des Sciences site Saint-Jérome.
ppm; C NMR (DMSO-d ): δ=184.70 (C=O), 163.58 (d,
6
1
J
= 244.05 Hz, C), 140.87 (CH), 136.83 (C), 133.0 (d,
CF
1
4
3
H NMR spectra were recorded on a BRUKER AC 300P
JCF =3.22 Hz, C), 129.65 (d, J =8.27 Hz, 2CH), 124.80
CF
1
3
(
300 MHz) spectrometer (Bruker, Bremen, Germany),
C
(CH), 123.64 (CH), 122.60 (CH), 121.08 (C), 117.43 (C),
2
NMR spectra on a BRUKER AC 300 P (75 MHz, Bruker)
115.71 (d, J =21.60 Hz, 2CH), 111.37 (CH), 49.0 (CH )
CF
2
1
spectrometer in DMSO-d . The H NMR chemical shifts
ppm.
6
were reported as parts per million downꢂeld from tetra-
1
3
methylsilane (Me Si), and the C NMR chemical shifts
1‑[3‑(Trifluoromethyl)benzyl]‑1H‑indole‑3‑carbaldehyde
(6d, C H F NO) Yield: 93%; white solid; m.p.: 134.8–
4
were referenced to the solvent peaks: DMSO-d (39.6 ppm).
6
17 12
3
1
Silica gel 60 (Merck, 230–400 mesh) was used for column
chromatography: thin-layer chromatography was performed
with silica gel Merck 60F-254 (0.25 mm layer thickness).
135.6 °C; H NMR (DMSO-d ): δ=10 (s, 1H, CHO), 8.57
6
(s, 1H, indole H-2), 8.17–8.14 (m, 1H, Ar–H), 7.81 (s, 1H,
Ar–H), 7.71–7.58 (m, 4H, Ar–H), 7.33–7.25 (m, 2H, Ar–H),
1
3
5
.70 (s, 2H, CH ) ppm; C NMR (DMSO-d ): δ=184.70
2
6
General procedure for the preparation
of compounds 6a–6e
(C=O), 138.41 (CH), 137.29 (C), 136.52 (C), 131.33 (q,
2
J
=33 Hz, C-CF ), 130.3 (CH), 129.82 (CH), 125.51(C),
CF
3
4
1
25.37 (q, J = 3.9 Hz, CH), 124.50 (CH), 123.85 (q,
CF
3
1
H-Indole-3-carbaldehyde (4, 1.45 g, 0.01 mol), the appro-
J
= 3.8 Hz, CH), 123.34 (CH), 122.34 (CH), 122.0 (q,
CF
1
priate benzyl chloride 6a–6e (0.011 mol), and 2.76 g anhy-
JCF = 272.35 Hz, C-F), 118.82 (C), 111.20 (CH), 50.47
3
drous K CO (0.02 mol) in 30 cm N,N-dimethylformamide.
(CH ) ppm.
2
3
2
The reaction mixture was reꢁuxed for 2 h. Progress of the
reaction was monitored by thin-layer chromatography. Upon
cooling to room temperature, the mixture was poured into
ice-cold water, and then, the precipitate was collected by ꢂl-
tration and dried. The crude product was puriꢂed by recrys-
tallization from ethanol to give solids 6a-6e in good yields.
1‑(2‑Cyanobenzyl)‑1H‑indole‑3‑carboxaldehyde (6e,
C H N O) Yield: 95%; white solid; m.p.: 147.8–148.2 °C;
1
7 12 2
1
H NMR (DMSO-d ): δ = 10 (s, 1H, CHO), 8.45 (s, 1H,
6
indole H-2), 8.20–8.17 (m, 1H, Ar–H), 7.97 (1H, dd,
J = 1.26 Hz, 7.58 Hz, Ar–H), 7.67 (1H, td, J = 1.42 Hz,
7
.74 Hz, Ar–H), 7.60–7.52 (m, 2H, Ar–H), 7.35–7.25 (m,
1
‑Benzyl‑1H‑indole‑3‑carbaldehyde (6a, C H NO) Yield:
2H, Ar–H), 7.07 (1H, d, J = 7.58 Hz, Ar–H), 5.83 (s, 2H,
1
6 13
1
13
9
0%; white solid; m.p.: 107.9–108.2 °C; H NMR (DMSO-
CH ) ppm; C NMR (DMSO-d ): δ=185.00 (C=O), 141.25
2
6
d ): δ=9.98 (s, 1H, CHO), 8.51 (s, 1H, indole H-2), 8.17–
(C), 140.0 (C), 137.07 (CH), 133.84 (CH), 133.50 (CH),
128.71 (CH), 127.81 (CH), 124.67 (CH), 123.91 (CH),
122.79 (CH), 121.20 (C), 117.72 (C), 117.19 (C), 111.13
6
8
.14 (m, 1H, Ar–H), 7.64–7.60 (m, 1H, Ar–H), 7.40–7.20
1
3
(
m, 7H, Ar–H), 5.58 (s, 2H, CH ) ppm; C NMR (DMSO-
2
d ): δ=184.70 (C=O), 141.00 (C), 137 (CH), 136.74 (C),
(C), 110.39 (CH), 48.19 (CH ) ppm.
6
2
1
1
28.71 (2CH), 127.78 (CH), 127.23 (2CH), 124.78 (CH),
23.61 (CH), 122.5 (CH), 121.07 (C), 117.38 (C), 111.40
General procedure for the preparation
of compounds 7a–7j
(
CH), 49.78 (CH ) ppm.
2
4
1
‑(3‑Chlorobenzyl)‑1H‑indole‑3‑carbaldehyde (6b,
To a solution of N -substituted thiosemicarbazide 3a, 3b
1
3
C H ClNO) Yield: 93%; white solid; m.p.: 80.4–80.8 °C; H
(6 mmol, 1 eq) in 33 cm ethanol, 3-(4-substitutedphenyl)-
16 12
NMR (DMSO-d ): δ=10 (s, 1H, CHO), 8.54 (s, 1H, indole
1H-indole-3-carbaldehyde 6a–6e (6.3 mmol, 1.05 eq) and
6
3
H-2), 8.19–8.12 (m, 1H, Ar–H), 7.68–7.61 (m, 1H, Ar–H),
0.50 cm acetic acid were added with stirring and the
7.45 (s, 1H, Ar–H), 7.44–7.35 (m, 2H, Ar–H), 7.33–7.25 (m,
resulting reaction mixture was stirred at 90 °C for 3 h.
1
3

982
A. Benmohammed et al.
The reaction was monitored by thin-layer chromatogra-
phy (TLC) for completion. The solid separated was then
ꢂltered and recrystallized from ethanol-DMF (3:1) to give
compounds 7a–7j.
(E)‑1‑[[1‑[3‑(Trifluoromethyl)benzyl]‑1H‑indol‑3‑yl]‑
m e t h y l e n e ] ‑ 4 ‑ p h e n y l t h i o s e m i c a r b a z i d e ( 7 d ,
C H F N S) Yield: 86%; white solid; m.p.: 188.3–188.9 °C;
2
4 19 3 4
IR (ATR): v⃗=3340 and 3141 (NH), 1538 (C=N), 1278 and
−
1 1
1
195 (C=S) cm ; H NMR (DMSO-d ): δ=11.61 (s, 1H,
6
(E)‑1‑[(1‑Benzyl‑1H‑indol‑3‑yl)methylene]‑4‑phenylthiosem‑
NH), 9.63 (s, 1H, NH), 8.43 (s, 1H, Ar–H), 8.29 (dd, 1H,
J=6.8 Hz, 1.3 Hz, Ar–H), 8.15 (s, 1H, CH=N), 7.72–7.62
(m, 4H, Ar–H), 7.60–7.50 (m, 3H, Ar–H), 7.41–7.35 (m, 2H,
icarbazide (7a, C H N S) Yield: 94%; white solid; m.p.:
2
3 20 4
2
00–200.5 °C; IR (ATR): v⃗ = 3342 and 3124 (NH), 1538
−
1 1
(
C=N), 1202 and 1272 (C=S) cm ; H NMR (DMSO-d ):
Ar–H), 7.27–7.17 (m, 3H, Ar–H), 5.59 (s, 2H, PhCH ) ppm;
6
2
1
3
δ=11.61 (s, 1H, NH), 9.63 (s, 1H, NH), 8.43 (s, 1H, indole
C NMR (DMSO-d ): δ=175.6 (C=S), 156.30 (C), 140.85
6
H-2), 8.26 (dd, 1H, J = 6.60 Hz, 1.4 Hz, Ar–H), 8.10 (s,
(CH), 139.47 (C), 137.28 (C), 134.57 (CH), 132.70 (C),
2
1
H, CH=N), 7.65 (d, 2H, J=8.62 Hz, Ar–H), 7.53 (dd, 1H,
131.7 (CH), 130.32 (CH), 129.54 (q, J =32 Hz, C-CF ),
CF
3
3
J=7.15 Hz, 1.1 Hz, Ar–H), 7.18–7.41 (m, 10H, Ar–H), 5.48
127.77 (2CH), 125.17 (C), 124.90 (q, J =4.0 Hz, CH),
CF
1
3
4
(
s, 2H, PhCH ) ppm; C NMR (DMSO-d ): δ=175 (C=S),
124.26 (q, J =3.8 Hz, CH), 123.55 (CH), 122.93 (CH),
2
6
CF
1
1
41.14 (CH), 139.75 (C), 137.90 (C), 137.38 (C), 134.71
122.75 (q, J = 272.35 Hz, C-F), 121.65 (CH), 113.77
CF
(
(
(
CH), 129.12 (2CH), 128.61 (2CH), 128.07 (CH), 127.64
2CH), 125.60 (2CH), 125.44 (CH), 125.23(C), 123.38
CH), 122.63 (CH), 121.56 (CH), 111.20 (CH), 111.12 (C),
(2CH), 111.5 (C), 111.0 (CH), 55.72 (OCH ), 49.20 (CH )
3
2
ppm.
4
9.90 (CH ) ppm.
(E)‑1‑[[1‑(2‑Cyanobenzyl)‑1H‑indol‑3‑yl]methylene]‑4‑phe‑
nylthiosemicarbazide (7e, C H N S) Yield: 90%; white
2
2
4 19 5
(
E)‑1‑[[1‑(3‑Chlorobenzyl)‑1H‑indol‑3‑yl]methylene]‑4‑phe‑
solid; m.p.: 221.7–222.1 °C; IR (ATR): v⃗=3305 and 3147
−
1 1
nylthiosemicarbazide (7b, C H ClN S) Yield: 87%; white
(NH), 1536 (C=N), 1265 and 1198 (C=S) cm ; H NMR
2
3
19
4
solid; m.p.: 178.4–178.9 °C; IR (ATR): v⃗=3343 and 3143
(DMSO-d ): δ=11.63 (s, 1H, NH), 9.65 (s, 1H, NH), 8.43 (s,
6
−
1 1
(
(
(
NH), 1541 (C=N), 1268 and 1204 (C=S) cm ; H NMR
1H, Ar–H), 8.33–8.31 (m, 1H, Ar–H), 8.04 (s, 1H, CH=N),
7.92 (dd, 1H, J=7.70 Hz, 1.10 Hz, Ar–H), 7.66–7.60 (m,
3H, Ar–H), 7.53–7.48 (m, 2H, Ar–H), 7.41–7.36 (m, 2H,
Ar–H), 7.28–7.18 (m, 3H, Ar–H), 7.00 (d, 1H, J=7.70 Hz,
DMSO-d ): δ=11.63 (s, 1H, NH), 9.64 (s, 1H, NH), 8.43
6
s, 1H, indole H-2), 8.28 (dd, 1H, J=6.7 Hz, 1.3 Hz, Ar–H),
8
.12 (s, 1H, CH=N), 7.64 (dd, 2H, J = 8.25 Hz, 0.83 Hz,
1
3
Ar–H), 7.55 (dd, 1H, J = 8.25 Hz, 1.28 Hz, Ar–H), 7.41–
Ar–H), 5.72 (s, 2H, PhCH ) ppm; C NMR (DMSO-d ):
2
6
7
2
1
.32 (m, 5H, Ar–H), 7.27–7.17 (m, 4H, Ar–H), 5.50 (s,
δ= 175 (C=S), 141.16 (C), 141 (CH), 139.75 (C), 137.52
(C), 134.87 (CH), 134.28 (CH), 133.89 (CH), 129.05 (CH),
128.61 (2CH), 128.14 (CH), 125.70 (2CH), 125.50 (CH),
125.14 (CH), 123.73 (CH), 122.88 (CH), 121.86 (CH),
1
3
H, PhCH ) ppm; C NMR (DMSO-d ): δ = 175 (C=S),
2
6
41.09 (CH), 139.75 (C), 137.28 (C), 137.69 (C), 133.72
(
CH), 131.1 (2CH), 128.61 (2CH), 128.07 (CH), 127.45
CH), 126.32 (CH), 125.67 (2CH), 125.19 (C), 123.55 (CH),
(
117.75 (C), 111.68 (C), 111 (CH), 110.75 (C), 49.16 (CH )
2
1
22.76 (CH), 121.70 (CH), 111.36 (C), 111.11 (CH), 49.16
ppm.
(
CH ) ppm.
2
(
E)‑1‑[(1‑Benzyl‑1H‑indol‑3‑yl)methylene]‑4‑(4‑methoxy‑
(
E) ‑ 1 ‑ [ [ 1 ‑ ( 4 ‑ F l u o r o r o b e n z y l ) ‑ 1 H‑ i n d o l ‑ 3 ‑ y l ] ‑
phenyl)thiosemicarbazide (7f, C H N OS) Yield: 95%;
2
4 22 4
m e t h y l e n e ] ‑ 4 ‑ p h e n y l t h i o s e m i c a r b a z i d e ( 7 c ,
white solid; m.p.: 252.9–253.2 °C; IR (ATR): v⃗=3285 and
−
1 1
C H FN S) Yield: 95%; white solid; m.p.: 193.5–193.9 °C;
3160 (NH), 1538 (C=N), 1260 and 1191 (C=S) cm ; H
23
19
4
IR (ATR): v⃗ = 3292 and 3160 (NH), 1537 (C=N), 1268
NMR (DMSO-d ): δ=11.52 (s, 1H, NH), 9.50 (s, 1H, NH),
6
−
1 1
and 1196 (C=S) cm ; H NMR (DMSO-d ): δ = 11.61
8.40 (s, 1H, indole H-2), 8.28 (dd, 1H, J=7.00 Hz, 1.0 Hz,
Ar–H), 8.10 (s, 1H, CH=N), 7.52 (d, 1H, J = 7.52 Hz,
Ar–H), 7.46 (dt, 2H, J =3.4 Hz, 2.1 Hz Ar–H), 7.36–7.31
(m, 2H, Ar–H), 7.29–7.24 (m, 3H, Ar–H), 7.23–7.19 (m,
1H, Ar–H), 7.15 (dd, 1H, J=7.24 Hz, 1.1 Hz, Ar–H), 6.93
6
(
s, 1H, NH), 9.62 (s, 1H, NH), 8.42 (s, 1H, indole H-2),
.28 (dd, 1H, J = 6.7 Hz, 1.3 Hz, Ar–H), 8.10 (s, 1H,
CH=N), 7.64 (dd, 2H, J = 8.25 Hz, 0.83 Hz, Ar–H), 7.55
dd, 1H, J = 8.25 Hz, 1.28 Hz, Ar–H), 7.41–7.32 (m, 5H,
8
(
Ar–H), 7.27–7.17 (m, 4H, Ar–H), 5.46 (s, 2H, PhCH )
(dt, 2H, J = 3.48 Hz, 2.2 Hz Ar–H), 5.47 (s, 2H, PhCH ),
2
2
1
3
13
ppm; C NMR (DMSO-d ): δ = 175.03 (C=S), 163.64
3.77 (s, 3H, OCH ) ppm; C NMR (DMSO-d ): δ=175.52
6
3
6
1
(
d, J = 243.2 Hz, C), 141.12 (CH), 139.74 (C), 137.26
(C=S), 157.3 (C), 141 (CH), 137.92 (C), 137.33 (C), 134.58
(CH), 132.67 (C), 129.12 (3CH), 128.07 (CH), 127.75 (CH),
127.64 (3CH), 125.19 (C), 123.36 (CH) 122.74 (CH),
CF
4
(
C), 134.60 (CH), 134.13 (d, J =3.30 Hz, C), 129.88 (d,
CF
CF
3
J
=8.48 Hz, 2CH), 128.61 (3CH), 125.62 (2CH), 125.46
(
CH), 125.23 (C), 123.43 (CH), 122.67 (CH), 121.62 (CH),
121.50 (CH), 113.77 (2CH), 111.15 (C), 55.72 (OCH ),
3
2
1
16.07 (d, J =21.46 Hz, 2CH), 111.20 (CH), 49.12 (CH )
49.86 (CH ) ppm.
CF
2
2
ppm.
1
3

Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in…
983
(
E ) ‑ 1 ‑ [ [ 1 ‑ ( 3 ‑ C h l o r o b e n z y l ) ‑ 1 H ‑ i n d o l ‑ 3 ‑ y l ] ‑
121.65 (CH), 113.77 (2CH), 111.5 (C), 111.0 (CH), 55.72
(OCH ), 49.20 (CH ) ppm.
methylene]‑4‑(4‑methoxyphenyl)thiosemicarbazide (7g,
3
2
C H ClN OS) Yield: 95%; white solid; m.p.: 237.7–
2
4
21
4
2
1
38.5 °C; IR (ATR): v⃗=3310 and 3140 (NH), 1548 (C=N),
( E ) ‑ 1 ‑ [ [ 1 ‑ ( 2 ‑ C y a n o b e n z y l ) ‑ 1 H ‑ i n d o l ‑ 3 ‑ y l ] ‑
methylene]‑4‑(4‑methoxyphenyl)thiosemicarbazide (7j,
C H N OS) Yield: 95%; white solid; m.p.: 271.9–272.3 °C;
−
1 1
273 and 1195 (C=S) cm ; H NMR (DMSO-d ): δ=11.53
6
(
s, 1H, NH), 9.51 (s, 1H, NH), 8.41 (s, 1H, indole H-2), 8.29
25 21 5
(
dd, 1H, J=7.15 Hz, 0.73 Hz, Ar–H), 8.10 (s, 1H, CH=N),
IR (ATR): v⃗=3312 and 3163 (NH), 1550 (C=N), 1274 and
−
1 1
7
2
.53 (d, 1H, J=7.70 Hz, Ar–H), 7.46 (dt, 2H, J= 3.4 Hz,
1189 (C=S) cm ; H NMR (DMSO-d ): δ=11.54 (s, 1H,
6
.2 Hz, Ar–H), 7.27–7.18 (m, 2H, Ar–H), 7.15 (dd, 1H,
NH), 9.51 (s, 1H, NH), 8.41 (s, 1H, Ar–H), 8.31 (dd, 1H,
J=7.0 Hz, 1.4 Hz, Ar–H), 8.02 (s, 1H, CH=N), 7.93 (dd,
1H, J=7.70 Hz, 1.10 Hz, Ar–H), 7.53–7.42 (m, 4H, Ar–H),
7.27–7.17 (m, 2H, Ar–H), 7.0–6.93 (m, 3H, Ar–H), 5.72 (s,
J=7.24 Hz, 1.0 Hz, Ar–H), 6.93 (dt, 2H, J=3.4 Hz, 2.2 Hz,
1
3
Ar–H), 5.5 (s, 2H, PhCH ), 3.77 (s, 3H, OCH ) ppm;
C
2
3
NMR (DMSO-d ): δ = 175.57 (C=S), 157.3 (C), 140.86
6
1
3
(
CH), 140.38 (C), 137.25 (C), 134.55 (CH), 133.72 (C),
33.72 (C), 132.67 (C), 131.1 (CH), 128.07 (CH), 127.78
2CH), 127.44 (CH), 126.33 (C), 125.17 (CH), 123.53 (CH),
22.85 (CH), 121.64 (CH), 113.8 (CH), 111.4 (C), 111.06
CH), 55.72 (OCH ), 49.16 (CH ) ppm.
2H, PhCH ), 3.77 (s, 3H, OCH ) ppm; C NMR (DMSO-
6
2 3
1
d ): δ=175.65 (C=S), 157.32 (C), 141.21 (C), 140.77 (CH),
(
137.50 (C), 134.73 (CH), 134.28 (CH), 133.89 (CH), 132.68
(C), 129.04 (CH), 128.10 (CH), 127.80 (2CH), 125.11 (C),
123.7 (CH), 1230 (CH), 121.80 (CH), 117.76 (C), 113.78
1
(
3
2
(
3CH), 111.73 (C), 110.72 (C), 55.72 (OCH ), 49.16 (CH )
3 2
(
E ) ‑ 1 ‑ [ [ 1 ‑ ( 4 ‑ F l u o r o b e n z y l ) ‑ 1 H ‑ i n d o l ‑ 3 ‑ y l ] ‑
ppm.
methylene]‑4‑(4‑methoxyphenyl)thiosemicarbazide (7h,
C H FN OS) Yield: 91%; white solid; m.p.: 239.6–
General procedure for the preparation
of compounds 9a–9j
2
4
21
4
2
1
40.4 °C; IR (ATR): v⃗=3313 and 3159 (NH), 1547 (C=N),
−
1 1
274 and 1195 (C=S) cm ; H NMR (DMSO-d ): δ=11.53
6
3
(
s, 1H, NH), 9.51 (s, 1H, NH), 8.41 (s, 1H, indole H-2), 8.29
A mixture of compound 7a–7j (3 mmol, 1 eq), 0.36 cm
(
dd, 1H, J=7.15 Hz, 0.83 Hz, Ar–H), 8.10 (s, 1H, CH=N),
ethyl 2-bromoacetate (1.1 eq) and 1 g anhydrous sodium
3
7
2
3
2
.53 (d, 1H, J=7.70 Hz, Ar–H), 7.46 (dt, 2H, J= 3.4 Hz,
.2 Hz, Ar–H), 7.39–7.32 (m, 3H, Ar–H), 7.27–7.15 (m,
H, Ar–H), 6.93 (dt, 2H, J=3.4 Hz, 2.2 Hz, Ar–H), 5.5 (s,
acetate (6 mmol, 2 eq) in 30 cm ethanol was stirred until
reꢁux; the mixture was stirred under the same conditions
until complete reaction (3–4 h). The reaction mixture was
left to cool, and poured into ice-cold water, and the sepa-
rated solid was ꢂltered, washed with water, and recrystal-
lized from a mixture of ethanol.
1
3
H, PhCH ), 3.77 (s, 3H, OCH ) ppm; C NMR (DMSO-
2
3
1
d ): δ = 175.6 (C=S), 163.64 (d, J = 243.75 Hz, C-F),
6
CF
1
57.31 (C), 140.87 (C), 137.27 (C), 134.42 (CH), 134.14
4
3
(
d, J =2.75 Hz, C), 132.70 (C), 129.88 (d, J =8.25 Hz,
CF
CF
2
CH), 127.67 (2CH), 125.25 (CH), 123.40 (CH), 122.75
2‑[2‑[(1‑Benzyl‑1H‑indol‑3‑yl)methylene]hydrazono]‑3‑phe‑
nylthiazolidin‑4‑one (9a, C H N OS) Yield: 94%; white
2
(
CH), 121.54 (CH), 115.78 (d, J = 21.46 Hz, 2CH),
CF
25 20 4
1
13.80 (2CH), 111.3 (C), 111.11 (CH), 55.74 (OCH ), 49.12
solid; m.p.: 250.9–251.4 °C; IR (ATR): v⃗ = 1715 (C=O),
3
−1 1
(
CH ) ppm.
1573 and 1530 (C=N), 1337 (NCS) cm ; H NMR (DMSO-
2
d ): δ=8.84 (s, 1H, CH=N), 8.26 (m, 1H, Ar–H), 7.95 (s,
6
(
E)‑1‑[[1‑[3‑(Trifluoromethyl)benzyl]‑1H‑indol‑3‑yl]‑
1H, CH=C), 7.52–7.41 (m, 6H,Ar–H), 7.28–7.24 (m, 7H,
1
3
methylene]‑4‑(4‑methoxyphenyl)thiosemicarbazide (7i,
Ar–H), 5.46 (s, 2H, PhCH ), 4.10 (s, 2H, CH ) ppm;
C
2
2
C H F N OS) Yield: 92%; white solid; m.p.: 232.3–
NMR (DMSO-d ): δ = 172.52 (C=O), 161.43(C), 153.72
2
5
21
3
4
6
2
1
32.8 °C; IR (ATR): v⃗=3316 and 3156 (NH), 1545 (C=N),
(CH), 137.85 (C), 137.49 (C), 135.68 (C), 135.40 (CH),
129.55 (2CH), 129.12 (3CH), 128.74 (2CH), 128.07 (CH),
127.60 (2CH), 125.64 (C), 123.47 (CH), 122.76 (CH),
−1 1
273 and 1193 (C=S) cm ; H NMR (DMSO-d ): δ=11.54
6
(
s, 1H, NH), 9.51 (s, 1H, NH), 8.41 (s, 1H, Ar–H), 8.31 (d,
1
H, J=7.34 Hz, Ar–H), 8.14 (s, 1H, CH=N), 7.70 (s, 1H,
121.71 (CH), 112.00 (C), 111.36 (CH), 49.88 (CH ), 32.68
2
Ar–H), 7.65 (d, 1H, J=7.70 Hz, Ar–H), 7.60–7.50 (m, 3H,
(CH ) ppm.
2
Ar–H), 7.44 (d, 2H, J=9.0 Hz, Ar–H), 7.27–7.15 (m, 2H,
Ar–H), 6.94 (d, 2H, J=9.0 Hz, Ar–H), 5.59 (s, 2H, CH ),
2‑[2‑[[1‑(3‑ Chlorobenz yl)‑1H‑indol‑3‑yl]methyl‑
ene]hydrazono]‑3‑phenylthiazolidin‑4‑ one (9b,
C H ClN OS) Yield: 87%; yellow solid; m.p.: 221.4–
2
1
3
3
.77 (s, 3H, OCH ) ppm; C NMR (DMSO-d ): δ=175.6
3
6
(
C=S), 156.30 (C), 140.85 (CH), 139.47 (C), 137.28 (C),
2
5
19
4
1
34.57 (CH), 132.70 (C), 131.7 (CH), 130.32 (CH), 129.54
221.9 °C; IR (ATR): v⃗ = 1718 (C=O), 1573 and 1529
2
−1 1
(
(
(
q, J =32 Hz, C-CF ), 127.77 (2CH), 125.17 (C), 124.90
(C=N), 1339 (NCS) cm ; H NMR (DMSO-d ): δ=8.46
CF
3
6
3
4
q, J =4.0 Hz, CH), 124.26 (q, J =3.8 Hz, CH), 123.55
(s, 1H, CH=N), 8.30–8.27 (m, 1H, Ar–H), 7.98 (s, 1H,
CF
CF
1
CH), 122.93 (CH), 122.75 (q, J = 272.35 Hz, C-F),
CH=C), 7.54 (t, 3H, J = 7.24 Hz, Ar–H), 7.48 (d, 1H,
CF
1
3

984
A. Benmohammed et al.
J=7.00 Hz, Ar–H), 7.41 (d, 2H, J =7.43 Hz, Ar–H), 7.34
t, 3H, J=4.68 Hz, Ar–H), 7.25 (t, 2H, J=3.76 Hz, Ar–H),
.21–7.1 (m, 1H, Ar–H), 5.50 (s, 2H, PhCH ), 4.11 (s, 2H,
7.41 (d, 1H, J=1 Hz, Ar–H), 7.29–7.23 (m, 2H, Ar–H), 5.70
1
3
(
(s, 2H, N-CH ), 4.11 (s, 2H, CH ) ppm; C NMR (DMSO-
2 2
7
d ): δ=172.30 (C=O), 153.56 (CH), 141 (C), 137.73 (C),
2
6
13
CH ) ppm; C NMR (DMSO-d ): δ=172.52 (C=O), 153.61
135.80 (CH), 135.52 (CH), 135.27 (C), 134.13 (CH), 133.88
(CH), 129.42 (2CH), 129.05 (C), 128.91 (CH), 128.88
(2CH), 128.37 (CH), 128.08 (CH), 125.81 (C), 123.71 (CH),
122.90 (CH), 121.92 (C), 117.58 (C), 112.66 (C), 111.0
(CH), 48.40 (CH ), 32.67 (CH ) ppm.
2
6
(
CH), 140.4 (C), 137.57 (C), 135.81 (C), 135.13 (C), 135.34
(
CH), 133.81 (C), 131.0 (CH), 129.55 (2CH), 129.03 (CH),
1
1
28.76 (2CH), 128.05 (CH), 127.43 (CH), 126.23 (CH),
25.81 (C), 123.56 (CH), 122.83 (CH), 121.78 (C), 112.38
2
2
(
CH), 111.16 (C), 49.29 (CH ), 32.66 (CH ) ppm.
2 2
2
‑ [ 2 ‑ [ ( 1 ‑ B e n z y l ‑ 1 H ‑ i n d o l ‑ 3 ‑ y l ) m e t h y l e n e ] ‑
2
‑[2‑[[1‑(4‑Fluorobenz yl)‑1H‑indol‑3‑yl]methyl‑
hydrazono]‑3‑(4‑methoxyphenyl)thiazolidin‑4‑one (9f,
ene]hydrazono]‑3‑phenylthiazolidin‑4‑ one (9c,
C H N O S) Yield: 90%; white solid; m.p.: 271.6–
2
6 22 4 2
C H FN OS) Yield: 91%; white solid; m.p.: 263.8–
272.0 °C; IR (ATR): v⃗ = 1716 (C=O), 1561 and 1531
2
5
19
4
−1 1
2
64.2 °C; IR (ATR): v⃗ = 1711 (C=O), 1562 and 1531
(C=N), 1343 (NCS) cm ; H NMR (DMSO-d ): δ=8.46 (s,
6
−1 1
(
C=N), 1337 (NCS) cm ; H NMR (DMSO-d ): δ=8.45 (s,
1H, CH=N), 8.30–8.26 (m, 1H, Ar–H), 7.91 (s, 1H, CH=C),
8.53–8.50 (m, 1H, Ar–H), 7.35–7.28 (m, 5H, Ar–H), 7.26–
7.19 (m, 4H, Ar–H), 7.05 (dt, 2H, J=9.8 Hz, 3.0 Hz, Ar–H),
5.46 (s, 2H, N-CH ), 4.07 (s, 2H, CH ), 3.8 (s, 3H, OCH )
6
1
7
7
H, CH=N), 8.30–8.25 (m, 1H, Ar–H), 7.95 (s, 1H, C=CH),
.58–7.51 (m, 3H, Ar–H), 7.49–7.40 (m, 3H, Ar–H), 7.33–
.26 (m, 2H, Ar–H), 7.26–7.12 (m, 4H, Ar–H), 5.46 (s, 2H,
2
2
3
1
3
13
N-CH ), 4.10 (s, 2H, CH ) ppm; C NMR (DMSO-d ):
ppm; C NMR (DMSO-d ): δ=172.42 (C=O), 169.54 (C),
2
2
6
6
1
δ=172.50 (C=O), 163.62 (d, J =243.2 Hz, C), 163.62
162.30 (C), 153.50 (CH), 137.83 (C), 137.67 (C), 135.11
(CH), 129.77 (2CH), 129.07 (2CH), 128.39 (C), 128.02
(CH), 127.59 (2CH), 125.83 (C), 123.40 (CH), 122.78 (CH),
121.61 (CH), 114.80 (2CH), 112.20 (C), 111.22 (CH), 55.59
(CH ), 50.01 (CH ), 32.67 (CH ) ppm.
CF
(
C),153.68 (CH), 137.41 (CH), 135.71 (C), 135.24 (CH),
4
3
1
2
34.13 (d, J = 3.30 Hz, C), 129.82 (d, J = 8.25 Hz,
CF
CF
CH), 129.53 (2CH), 129.03 (CH), 128.76 (2CH), 125.68
(
C), 123.49 (CH), 122.80 (CH), 121.75 (CH), 116.07 (d,
3
2
2
2
J
= 21.46 Hz, 2CH), 112.1 (CH), 111.3 (CH), 49.07
CF
(
CH ), 32.70 (CH ) ppm.
2‑[2‑[[1‑(3‑Chlorobenzyl)‑1H‑indol‑3‑yl]methylene]‑
hydrazono]‑3‑(4‑methoxyphenyl)thiazolidin4‑one (9g,
C H ClN O S) Yield: 91%; white solid; m.p.: 192.0–
2
2
2
‑[2‑[[1‑[3‑(Trifluoromethyl)benzyl]‑1H‑indol‑3‑yl]‑
2
6
21
4 2
methylene]hydrazono]‑3‑phenylthiazolidin‑4‑one (9d,
192.6 °C; IR (ATR): v⃗ = 1717 (C=O), 1576 and 1531
−1 1
C H F N OS) Yield: 86%; green solid; m.p.: 208.7–
(C=N), 1329 (NCS) cm ; H NMR (DMSO-d ): δ=8.45 (s,
2
6
19
3
4
6
2
09.6 °C; IR (ATR): v⃗ = 1718 (C=O), 1561 and 1531
1H, CH=N), 8.31–8.28 (m, 1H, Ar–H), 7.94 (s, 1H, CH=C),
7.54–7.51 (m, 1H, Ar–H), 7.38–7.27 (m, 5H, Ar–H), 7.27–
7.17 (m, 3H, Ar–H), 7.06 (dd, 2H, J= 9.8 Hz, J = 3.0 Hz,
Ar–H), 5.50 (s, 2H, N-CH ), 4.08 (s, 2H, CH ), 3.84 (s,
−1 1
(
C=N), 1364 (NCS) cm ; H NMR (DMSO-d ): δ=8.47 (s,
6
1
7
7
H, CH=N), 8.32–8.29 (m, 1H, Ar–H), 8.00 (s, 1H, CH=C),
.64 (d, 2H, J=10.82 Hz, Ar–H), 7.57–7.52 (m, 4H,Ar–H),
.74 (d, 2H, J = 7.0 Hz, Ar–H), 7.42 (d, 2H, J = 7.24 Hz,
2
2
1
3
3H, OCH ) ppm; C NMR (DMSO-d ): δ=172.52 (C=O),
3
6
Ar–H), 7.29–7.14 (m, 2H, Ar–H), 5.60 (s, 2H, N-CH ), 4.11
162.42 (C), 159.64 (C), 153.47 (CH), 140.41 (C), 137.58
(C), 135.07 (CH), 133.82 (C), 131.0 (CH), 129.77 (2CH),
128.38 (C), 128.05 (CH), 127.43 (CH), 126.23 (CH), 125.82
(C), 123.55 (CH), 122.84 (CH), 121.76 (CH), 114.80 (2CH),
112.42 (CH), 111.15 (C), 56.0 (CH ), 49.3 (CH ), 32.54
2
13
(
s, 2H, CH ) ppm; C NMR (DMSO-d ): δ=172.54 (C=O),
2
6
1
62.62 (C), 153.7 (CH), 139.40 (C), 137.41 (C), 135.66
(
C), 135.34 (CH), 131.64 (CH), 130.31 (CH), 129.66 (q,
2
J
=31.7 Hz, C-CF ), 129.55 (2CH), 129.07 (CH), 128.74
CF
3
3
2
3
(
2CH), 125.62 (C), 125.0 (q, J =3.7 Hz, CH), 124.2 (q,
(CH ) ppm.
2
CF
4
J
=3.6 Hz, CH), 123.66 (CH), 122.85 (CH), 122.70 (q,
CF
1
JCF =272.35 Hz, C-F), 121.88 (CH), 112.25 (CH), 111.23
2‑[2‑[[1‑(4‑Fluorobenzyl)‑1H‑indol‑3‑yl]methylene]‑
hydrazono]‑3‑(4‑methoxyphenyl)thiazolidin4‑one (9h,
C H FN O S) Yield: 95%; white solid; m.p.: 242.4–
(
C), 49.17 (CH ), 32.70 (CH ) ppm.
2
2
2
6
21
4 2
2
‑[2‑[[1‑(2‑ Cyanobenz yl)‑1H‑indol‑3‑yl]methyl‑
242.9 °C; IR (ATR): v⃗ = 1716 (C=O), 1573 and 1532
−
1 1
ene]hydrazono]‑3‑phenylthiazolidin‑4‑ one (9e,
(C=N), 1352 (NCS) cm ; H NMR (DMSO-d ): δ=8.44 (s,
6
C H N OS) Yield: 82%; white solid; m.p.: 264.9–265.6 °C;
1H, CH=N), 8.28–8.25 (m, 1H, Ar–H), 7.96 (s, 1H, CH=C),
7.56–7.54 (m, 1H, Ar–H), 7.34–7.27 (m, 4H, Ar–H), 7.25–
7.21 (m, 2H, Ar–H), 7.16 (d, 2H, J=8.9 Hz, Ar–H), 7.06
26 19 5
IR (ATR): v⃗ = 1718 (C=O), 1572 and 1531 (C=N), 1346
−
1 1
(
NCS) cm ; H NMR (DMSO-d ): δ=8.46 (s, 1H, CH=N),
6
8
.35–8.29 (m, 1H, Ar–H), 8.00 (s, 1H, CH=C), 7.87 (d, 1H,
J = 1 Hz, Ar–H),7.62 (td, 1H, J = 7.8 Hz, 1.4 Hz, Ar–H),
.56–7.46 (m, 10H, Ar–H), 7.43 (d, 1H, J=1.47 Hz, Ar–H),
(d, 2H, J = 8.9 Hz, Ar–H), 5.45 (s, 2H, N-CH ), 4.07 (s,
2
1
3
2H, CH ), 3.82 (s, 3H, OCH ) ppm; C NMR (DMSO-d ):
2
3
6
1
7
δ=172.66 (C=O), 163.62 (d, J =243.74 Hz, C-F), 162.78
CF
1
3

Synthesis and antimicrobial activities of new thiosemicarbazones and thiazolidinones in…
985
(
C), 159.54 (C), 153.54 (CH), 137.38 (C), 135.23 (CH),
cephalosporin), and gentamicin (aminoglycosides) are
used as standard antibacterial drugs. All the tested antibi-
otics were supplied from Oxoid.
4
1
34.11 (d, J = 2.75 Hz, C), 129.84 (2CH), 129.72 (d,
CF
3
J
=8.25 Hz, 2CH), 128.19 (C), 125.67 (C), 123.50 (CH),
CF
2
1
2
4
22.80 (CH), 121.75 (CH), 115.78 (d, J = 21.46 Hz,
The in vitro minimum inhibitory concentration (MIC)
of the various compounds against bacterial strains was
determined by the agar dilution method as recommended
by NCCLS [41]. DMSO was used to prepare differ-
CF
CH), 114.73 (2CH), 112.1 (C), 111.32 (CH), 55.85 (CH ),
3
9.07 (CH ), 32.60 (CH ) ppm.
2
2
3
2
‑[2‑[[1‑[3‑(Trifluoromethyl)benzyl]‑1H‑indol‑3‑yl]meth‑
ent concentrations ranging from 0.25 to 128 μg/cm by
ylene]hydrazono]‑3‑(4‑methoxyphenyl)thiazolidin‑4‑one
serial dilutions. Petri dishes were spot-inoculated with 2
3
4
(
9i, C H F N O S) Yield: 92%; white solid; m.p.: 186.7–
mm of each bacterial suspension (1 × 10 CFU/spot) and
incubated at 37 °C for 24 h. At the end of the incubation
period, MIC was determined as the lowest concentration
for the tested chemical that did not result in any visible
growth on the plate. A control test was also conducted
with DMSO media added to the same dilutions as used in
the experiment, to ensure that the solvent had no inꢁuence
on bacterial growth.
2
7 21 3 4 2
1
87.1 °C; IR (ATR): v⃗ = 1724 (C=O), 1563 and 1530
−1 1
(
C=N), 1328 (NCS) cm ; H NMR (DMSO-d ): δ=8.46 (s,
6
1
H, CH=N), 8.32–8.28 (m, 1H, Ar–H), 7.93 (s, 2H, CH=C),
7
.61 (t, 1H, J = 7.70 Hz, Ar–H), 7.49 (t, 2H, J= 6.70 Hz,
Ar–H), 7.31 (d, 2H, J = 8.62 Hz, Ar–H), 7.27–7.24 (m,
2
H, Ar–H), 7.06 (d, 2H, J= 8.62 Hz, Ar–H), 7.31 (d, 1H,
J=7.70 Hz, Ar–H), 5.72 (s, 2H, N-CH ), 4.08 (s, 2H, CH ),
2
2
1
3
3
.84 (s, 3H, OCH ) ppm; C NMR (DMSO-d ): δ=172.42
3
6
Supplementary Information The online version contains supplemen-
(
C=O), 162.47 (C), 159.64 (C), 153.47 (CH), 139.41 (C),
tary material available at https://doi.org/10.1007/s00706-021-02823-6.
1
1
37.60 (C), 135.05 (CH), 131.60 (CH), 130.24 (CH),
2
29.96 (q, J =31.36 Hz, C-CF ), 129.77 (2CH), 128.37
CF
3
Acknowledgements This work was supported by the CNRS (Centre
3
(
C), 125.82 (C), 124.83 (q, J =3.7 Hz, CH), 124.15 (q,
CF
National de la Recherche Scientiꢂque) and Aix-Marseille University.
3
J
=3.7 Hz, CH), 123.58 (CH), 122.86 (CH), 122.72 (q,
CF
1
JCF =272.35 Hz, C-F), 121.80 (CH), 114.8 (2CH), 112.50
(
C), 111.10 (CH), 56.0 (CH ), 49.34 (CH ), 32.54 (CH )
3
2
2
ppm.
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