Bioactive isatin (oxime)-triazole-thiazolidinedione ferrocene molecular conjugates: Design, synthesis and antimicrobial activities

Article abstract of DOI:10.1016/j.jorganchem.2021.121716

Molecular conjugates often combine the inherent properties of the individual components and exhibit a different characteristic feature. Introduction of an organometallic moiety can indeed augment the overall effect. This article narrates the synthesis of ferrocene appended isatin?2,4-thiazolidinedione molecular hybrid linked via a triazole moiety. Isatin and 2,4-thiazolidinedione were linked via a triazole unit formed by a simple copper catalysed alkyne-azide 1,3-dipolar cycloaddition reaction. The UV–vis and electrochemical studies on all the new compounds are reported. Antimicrobial activity against some selected gram-positive and gram-negative strains was also examined for all the new derivatives and compounds 6(b), 6(c), 6(h) and 6(i) revealed similar antimicrobial activity for all tested microbes and similar pattern to that of standard antibiotics.

Full text of DOI:10.1016/j.jorganchem.2021.121716

Journal of Organometallic Chemistry 937 (2021) 121716
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Bioactive isatin (oxime)-triazole-thiazolidinedione ferrocene molecular
conjugates: Design, synthesis and antimicrobial activities
Swetha Yagnama,d, Rajiv Trivedia,d,∗, Suman Krishnab, Lingamallu Giribabub,d
,
Ganji Praveenac, Reddy Shetty Prakashamc,d
a Catalysis and Fine Chemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India
b Polymer and Functional Materials Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India
c Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India
d Academy of Scientific and Innovative Research, AcSIR Headquarters, CSIR-HRDC campus Sector 19, Kamala Nehru Nagar, Ghaziabad, U.P. – 201002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Molecular conjugates often combine the inherent properties of the individual components and exhibit a
different characteristic feature. Introduction of an organometallic moiety can indeed augment the over-
all effect. This article narrates the synthesis of ferrocene appended isatin−2,4-thiazolidinedione molecular
hybrid linked via a triazole moiety. Isatin and 2,4-thiazolidinedione were linked via a triazole unit formed
by a simple copper catalysed alkyne-azide 1,3-dipolar cycloaddition reaction. The UV–vis and electro-
chemical studies on all the new compounds are reported. Antimicrobial activity against some selected
gram-positive and gram-negative strains was also examined for all the new derivatives and compounds
6(b), 6(c), 6(h) and 6(i) revealed similar antimicrobial activity for all tested microbes and similar pattern
to that of standard antibiotics.
Received 27 July 2020
Revised 13 January 2021
Accepted 19 January 2021
Available online 22 January 2021
Keywords:
Ferrocene-molecular conjugates
Isatin (Oxime)
1,2,3-Triazole
2,4-Thiazolidinedione
Electrochemistry
© 2021 Elsevier B.V. All rights reserved.
Antimicrobial activity
1. Introduction
1H-indole-2,3–dione (commonly known as Isatin), has three
different possibility of chemical modifications namely, N1, C3 and
Drug design using molecular hybridization approach, for devel-
oping new antimicrobial candidates that exhibit better activity, has
been gaining unprecedented attention [1]. An effective and com-
monly used direction for the exploration of novel and highly ac-
tive compounds relies on combining two or more different bioac-
tive molecules either having complementary pharmacophoric func-
tions or displaying variable mechanism of action against the mi-
crobial strain [2]. Quite often such type of hybrid drugs can have
potential to overcome the pharmacokinetic drawbacks encoun-
tered by a number of conventional drugs [3]. Towards this, certain
common heterocyclic fragments such as isatin, [4] 1,2,3-triazoles,
[5] and 2,4-thiazolidinediones, [6] have demonstrated potential
chemotherapeutic and antimicrobial activities as shown in (Fig. 1).
Moreover, there are several published reports on the use of triazole
tethered bi-functional hybrids and its role as a linker to join two
different bioactive functionalities [7].
C5 positions and also serves as a prominent scaffold for the de-
sign of several biologically active compounds [8]. These modifica-
tions result in several biological activities such as anti-cancer [9,10]
anti-oxidant [11], HIV reverse transcriptase inhibition [12,13], neu-
roprotective [14], anti-fungal [15], antidepressant, [16] anticonvul-
sant, [17] anti-bacterial [18], and antidiabetic [19]. Few of the C5
and C6 substituted isatin derivatives exhibited inhibition against
monoamine oxidase B and amongst them 5-(4-phenylbutyl) isatin
was found to be 18,500-fold more potent than the parent com-
pounds [12]. The C3 carbonyl group of isatin is highly reactive and
can be conveniently utilized for the construction of spirooxindole
framework [13–15]. As indicated in recent studies, isatin can in-
hibit the growth of SH-SY5Y cells as well as induce apoptosis via
an intrinsic apoptotic [20,21].
2,4-Thiazolidinedione, a sulphur, nitrogen and oxygen contain-
ing five-member heterocyclic moiety, also exhibits potential for
a
range of biological activities, often present in several drug
molecules and natural products [22]. These five member hetero-
cyclic systems have potency to reduce insulin resistance as well
as effective in the treatment of cardiovascular metabolic syndrome
[23]. Particularly, 4-thiazolidinones have exhibited various impor-
∗
Corresponding author: Catalysis and Fine Chemicals Division, CSIR-Indian In-
stitute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad, Telangana,
500007, India.
E-mail addresses: trivedi@iict.res.in, trivedi.iict@gov.in (R. Trivedi).
https://doi.org/10.1016/j.jorganchem.2021.121716
0022-328X/© 2021 Elsevier B.V. All rights reserved.

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Fig. 1. Some of the biologically active molecules of Isatin, 1H-1,2,3-triazoles and 2,4-thiazolidinedione.
tant biological activities such as anti-inflammatory, anti-tubercular,
antimicrobial, anticonvulsant, antiviral and anti-HIV [24].
ology. Interactions and effects of organometallic moieties conju-
gated to a bioactive component has developed as a full-fledged
research area [27]. Over the last few years, a close association
between classical organometallic chemistry and medicine, biology
and molecular biotechnology has emerged [28]. In recent years,
organometallic conjugates have become pivotal as medicinally im-
portant molecules which demonstrated their potential as new ther-
apeutic as well as diagnostic agents [29]. Moreover, the high stabil-
ity of the ferrocenyl group in water as well as its reversible electro-
Due to its metabolic stability and varied biological activities,
1H-1,2,3-triazole is often a preferable choice as a linker in the
molecular hybridization approach [25]. The enhanced biological ac-
tivities of the 1,2,3-triazole ring relies on a number of factors such
as moderate dipole character, hydrogen bonding capability, rigidity
as well as stability under in vivo conditions [26]. The construction
of bioconjugates via triazoles is an appealing synthetic method-
2

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Fig. 2. Illustration of the design strategy for triazole tethered isatin and 2,4 Thiazolidinedione.
chemistry has made ferrocene unit as a prominent organometallic
entity to conjugate with drugs and biomolecules [30]. In fact, sev-
eral bioorganometallic compounds exhibited anticancer properties,
however, interest in antimicrobial, anti-parasitic and antibacterial
activities of such compounds is gaining substantial attention.
The simple synthetic procedures and favourable electronic
properties of ferrocene derivatives contributed to their widespread
applications as sensors, [31] catalysts, [32] and electronic probes,
[33] as well as in the field of medicinal chemistry [34–37]. Fer-
rocifen, hydroxyferrocifen, ferrophanes and ferroquine are some of
the ferrocene derivatives well known for exhibiting anti-cancer and
anti-malarial activities [38–45].
as bioactive linkers. Some of these belong to amides, triazoles,
amide-triazoles, pseudo-peptides, sugar boronates, imidazolinones
and 2,4-thiazolidinediones to name a few [46]. In continuation
with our interest, the present work describes the synthesis, elec-
trochemical properties and in vitro antimicrobial evaluation of
1H-1,2,3-triazole tethered isatin-ferrocene-thiazolidinedione conju-
gates as depicted in Fig. 2.
2. Results and discussion
2.1. Synthesis and characterization
Over the past decade, our group has been involved in the
Scheme
1
illustrates the synthetic route followed for
synthesis, characterisation and biological evaluation of
a vari-
the preparation of the desired isatin (oxime)-triazole-2,4-
ety of ferrocene conjugates that include simple organic as well
thiazolidinedionehybrids, 6(a-j). Previously reported protocol was
3

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Scheme 1. Synthesis of triazole linked isatin- 2,4 Thiazolidinedione conjugates. Reagents and conditions: (a) Dibromoalkane, K2CO3, CH3CN, 2 h, rt; (b) NaN3, DMF, 3 h,
reflux; (c) NH2OH, NaOH, rt,1 h; (d) piperidine, ethanol, reflux; e) Propargyl bromide, K2CO3, DMF, rt; (f) Sodium ascorbate, CuSO4, THF:H2O, (1:1) 30 mins, rt.
4

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Scheme 2. Synthesis of Triazole linked isatin- 2,4 Thiazolidinedione, (E).
followed for the preparation of C5-substituted N-alkyl azido-isatins
(3), [47] wherein, an initial base promoted alkylation of isatin
(1) with dibromoalkanes forms the corresponding C5-substituted
N-alkyl bromoisatins (2) at room temperature in acetonitrile
solution. The subsequent treatment of (2) with sodium azide at
60°C resulted in the formation of the desired precursors (3) as
shown in (Scheme 1). The precursor, (3) reacts with hydroxyl
amine to give a N-alkylazido-hydxoxyiminoisatins (4). The desired
1H-1,2,3-triazole tethered isatin ferrocene conjugates, 6(a-j) were
obtained from the copper promoted alkyne-azide cycloaddition
reaction of compound (4) and ferrocenyl 2,4-thiazolidinedione
alkyne (5).
−29.7 ppm. All the compounds were characterized by the mass
spectra and elemental analysis. In the FT-IR spectra, the stretching
frequencies in the region 3152- 3140 cm−1 can be assigned to the
–
C H vibrations of the triazole ring, while the frequencies around
1680–1677 cm−1 are the characteristic C O stretching frequencies
=
[48].
2.2. UV–Vis spectroscopy
The isatin (oxime) derivatives exhibit characteristic UV–vis ab-
sorption spectra, wherein an increase in the intensity of the bands
in the 300 nm region is observed for the electron withdrawing
groups such as chloro and bromo substituted isatins [49]. Simi-
lar pattern can be expected from the isatin ferrocene conjugates,
6(a-j). The absorption spectra of ferrocenyl 2,4-thiazolidinedione
isatin-triazole conjugates, 6(a-j) were recorded in acetonitrile sol-
vent (Fig. 3). Two absorption maxima were observed at 332
and 505 nm for all the compounds. The bands constitute the
metal-to-ligand charge transfer [Fe(d)- Cp(π∗)] and the symme-
try forbidden [Fe(a1g)-Fe(e1g)] or d-d transition for the Fe of fer-
rocene, respectively. It was observed that the bands correspond-
ing to the Fe(a1g)→Fe(e1g) or d-d transitions were weak due to
the symmetry forbidden transitions, whereas the intensity of the
Fe(e2g))→Cp(e1g) or π→π∗ transitions bands was considerably
higher even at the concentration range of 0.1 mM. Furthermore,
these well resolved π-π∗ bands indicated that the ferrocene was
conjugated with the isatin moiety [50].
While preparing the ferrocenyl conjugates, a parent compound
(E) was also synthesised starting from the readily available 3,5-
dimethoxy benzaldehyde (A). Following a similar synthetic proto-
col as the ferrocene conjugates, the parent compound (E) was ob-
tained in moderate yield. (Scheme 2). The compound (E) was char-
acterised by 1H NMR, 13C NMR and mass analysis along with an-
timicrobial properties.
1H and 13C NMR spectroscopic characterisation of all the com-
pounds revealed the corresponding signal. The triazole proton sig-
nal for the triazoles 6(a-j) was observed around δ 7.67 ppm –
7.78 ppm in the 1H NMR spectra. The protons of the unsubsti-
tuted cyclopentadienyl (Cp) ring appeared as a singlet at δ 4.15
- 4.22 ppm, while those for the substituted cyclopentadienyl (Cp)
=
ring appeared around δ 4.51 ppm and 4.59 ppm. The N OH pro-
tons appeared as a broad singlet at around δ12.3 ppm −13.3 ppm.
–
In all the triazole compounds, 6(a-j), the isatin (oxime) N CH2
2.3. Electrochemical characterization
was observed as a multiplet around δ3.7–3.8 ppm. The olefinic
=
>C CH proton appeared as a singlet at about δ 7.71 ppm –
8.27 ppm, in the 1H NMR spectra for all the compounds, and the
characteristic peaks corresponding to the Tr-NCH2 protons were
observed at δ 4.37 ppm −4.43 ppm. In the 13C NMR spectra,
for all the triazoles, the carbonyl carbon of the ferrocene substi-
tuted 2,4-thiazolidinedione fragment appeared at δ 172–163 ppm
The cyclic voltammetry (CV) experiment was conducted in ace-
tonitrile for compounds 6(a-j) as shown in (Fig. 4). The redox po-
tential data of the triazole compounds 6(a-j) are summarized in
(Table 1). A 0.5 mM solution of the compounds was prepared
in acetonitrile solvent with 0.1 M tetrabutylammonium perchlo-
rate (TBAP) as a supporting electrolyte. The typical conventional
three-electrode cell consists of a glassy carbon as a working elec-
trode, a platinum wire as an auxiliary electrode and a standard
=
and the olefinic >C CH carbon appeared at δ 112.9–108.2 ppm,
while isatin (oxime) N CH2 carbon was observed at δ 36.4 ppm
–
5

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Table 1
CV and UV data for the isatin conjugated 2,4 Thiazolidinedione Triazole 6(a-j) ob-
tained from voltammograms (vs. SCE)a.
Compound code
Epa (mV)
Epc (mV)
࢞ Ep (mV)
E1/2 (mV)
ipa/ipc
6a
6b
6c
6d
6e
6f
694
658
773
688
696
707
671
673
668
690
550
577
616
573
580
612
605
560
532
592
144
81
622
617
694
585
638
659
638
616
600
641
1.33
0.85
0.75
1.13
0.92
1.08
0.92
1.05
1.29
0.93
157
115
116
95
6 g
6h
6i
66
113
136
98
6j
a
All the compounds in CH3CN with TBAP (supporting electrolyte) at 25 °C at a
scan rate of 100 mV s−1. E0ox = (Epc + Epa/2), ꢀEp = (Epa − Epc), ipa/ipc (ratio
between anodic and cathodic peak current).
timicrobial activity and the lowest activity was shown by the com-
pound 6(j). Similar trend has been noticed with selected fungal
strains (Candida albicans and Aspergillus oryzae). Hybrid aryl com-
pound (E) exhibited very less activity when compared to the syn-
thesized novel triazole conjugates (6(a-j)). The observed higher bi-
ological activity for the compound may be attributed to substituted
group of isatin ring and due to the combination of triazole and
ferrocene unit. Ferrocene and triazole compounds show interesting
antibacterial antifungal activities, as per previous reports [51a,b,c].
Based on the above results, the MIC of all the compounds were
further evaluated against the cultures used for the antimicrobial
activity as shown in (Table 3). A MIC value of 4 μg ml−1against
the bacterial strains and 32 μg ml−1 against the fungal strain was
obtained for the compounds 6(b), 6(c), 6(h) and 6(i). This obser-
vation is interesting to note that the tested compounds (6b), (6c),
(6 h), (6i) performed same activity with double the concentration
Fig. 3. UV–Vis spectra of triazole6(a-j) in acetonitrile at room temperature.
to that of streptomycin (2 μg mL–1) and Fluconazole (16 μg mL–1
)
3. Conclusion
In conclusion, a series of isatin-ferrocene conjugates have been
synthesized via Cu-promoted alkyne-azide cycloaddition reactions
and evaluated for their antimicrobial activities. Absorption spec-
troscopy and electrochemical studies have shown that the com-
pounds are stable in acetonitrile solvent. The compounds 6(b), 6(f),
6(g), 6(j) exhibited a reversible oxidation wave and the compounds
6(a), 6(c), 6(d), 6(e), 6(h), 6(i) exhibited quasi-reversible behaviour.
All the compounds demonstrated their characteristic transitions
Fe(a1g)→Cp(e2g) and Fe(a1g)→Fe(e1g) transitions) in the UV-
Visible spectra. All the synthesized triazole compounds exhibited
moderate to good antimicrobial activity. The antibacterial activity
of all the synthesized triazole conjugates 6(a-j) against both Gram-
positive (Bacillus subtilis, Bacillus megaterium, Mycobacterium smeg-
matis, Klebsiella pneumonia) and Gram-negative (Escherichia coli,
Salmonella typhi, Pseudomonas aeruginosa,Pseudomonas putida) bac-
terial strains were compared against Streptomycin. The in vitro an-
tifungal activity of all the synthesized triazole conjugates 6(a-j)
was studied against the two fungal strains (Candida albicans and
Aspergillus oryzae) and Fluconazole was used as a standard drug.
Fig. 4. Electrochemical oxidative potential curves of 6(a-j) in acetonitrile at room
temperature. All the compounds 6(a-j) in CH3CN with TBAP (supporting electrolyte)
at 25 °C at a scan rate of 100 mV s−1
.
Calomel electrode (SCE) as the reference electrode. The potential
was scanned with a scan rate of 100 mVs−1 over the range 200–
1100 mVs−1. A quasi-reversible redox couples of Fe(II)/Fe(III) were
obtained in the cyclic voltammograms of 6(a-j), as shown in Fig. 4.
The values of the half-wave potential (E1/2) are shown in (Table 1).
∼
The peak current ratio, ipa/ipc 1, with high peak separation, sim-
=
ilar to those reported in earlier literature was obtained for all the
ferrocene derivatives [48]. The oxidation potentials (Epa) for all the
isatin ferrocene hybrids, 6(a-j) were higher than the unsubstituted
ferrocene.
2.4. Biological activity
4. Experimental section
2.4.1. Anti microbial activity
The antibacterial profile of all the synthesized novel triazole
conjugates (6(a-j)) and aryl compound (E) is given in (Table 2).
The compounds 6(b), 6(c), 6(h) and 6(i) displayed excellent anti-
microbial activity towards all the test organisms and the values
were comparable to the standard compounds Streptomycin and
Flucanazole. While the compound 6(g) had good antimicrobial ac-
tivity, the compounds 6(a), 6(d), 6(e), 6(f) exhibited moderate an-
All reagent grade chemicals were purchased from Sigma–
Aldrich and used as supplied. The Thin Layer Chromatography
(TLC) was performed on Merck silica gel F254 plates using hexane
and ethylacetate as eluting agents. The products were character-
ized by 1H and 13C NMR and Mass (ESI) spectroscopy. All 1H and
13C NMR spectra were recorded in a mixture of (CDCl3+DMSO–
d6) solvents on Avance 300 or Avance 400 or Avance New 500
6

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
Table 2
Antimicrobial activity of compounds 6(a-j)a.
Gram-positive bacteria
Gram-negative bacteria
Fungal strains
Compounds
B.subtillis
B.megaterium
M.smegmatis
K. pneumoniae
E.coli
S. typhi
P.putida
P. arguinosa
C.albicans
A. oryzae
6a
14 0.4
19 0.2
20 0.2
13 0.4
13 0.4
12 0.4
17 0.2
18 0.2
19 0.4
14 0.4
10 0.2
21 0.2
0
12 0.3
21 0.2
20 0.3
13 0.4
13 0.4
14 0.2
16 0.4
19 0.2
21 0.4
12 0.4
11 0.4
22 0.2
0
15 0.4
20 0.2
22 0.2
16 0.4
15 0.4
15 0.3
15 0.3
21 0.2
20 0.4
12 0.4
11 0.3
25 0.2
0
12 0.4
20 0.3
21 0.2
14 0.3
17 0.4
13 0.4
17 0.2
19 0.2
20 0.4
12 0.4
11 0.4
22 0.2
0
15 0.3
19 0.3
18 0.2
15 0.4
15 0.3
14 0.3
16 0.2
20 0.2
19 0.4
13 0.4
10 0.3
21 0.2
0
10 0.4
18 0.2
19 0.3
12 0.4
12 0.4
11 0.4
15 0.3
19 0.3
21 0.4
10 0.4
10 0.2
21 0.2
0
16 0.3
21 0.2
19 0.2
16 0.4
16 0.3
13 0.4
15 0.4
21 0.2
19 0.4
14 0.4
10 0.2
23 0.2
0
12 0.4
19 0.2
19 0.3
13 0.4
12 0.4
15 0.4
11 0.4
18 0.2
19 0.4
12 0.4
11 0.2
20 0.2
0
15 0.4
20 0.3
19 0.2
14 0.4
12 0.2
16 0.3
16 0.4
20 0.3
20 0.4
14 0.4
10 0.3
21 0.2
0
13 0.3
20 0.2
20 0.3
16 0.4
15 0.2
15 0.3
17 0.2
20 0.2
19 0.4
13 0.4
11 0.4
22 0.2
0
6b
6c
6d
6e
6f
6 g
6h
6i
6j
E
Standard drugb
DMSO
a
Zone of inhibition by compounds against selected test organisms.
b
Streptomycin and Fluconazole were used as standard drug, respectively, for antibacterial and antifungal activity evaluation.
Table 3
MIC values of compounds 6(a-j) in μg mL–1
.
Minimum inhibitory concentration (μg mL–1) of compounds (6a-j)against the tested bacterial and fungal strains
Gram-positive bacteria Gram-negative bacteria
Fungal strains
Compounds
B.subtillis
B.megaterium
M.smegmatis
K. pneumoniae
E.coli
S. typhi
P.putida
P. arguinosa
C.albicans
A. oryzae
6a
32
4
64
4
32
4
64
4
32
4
64
4
32
4
64
4
32
4
64
32
32
64
64
64
16
32
32
64
64
16
6b
6c
4
4
4
4
4
4
4
4
4
6d
64
64
64
16
4
64
64
32
32
4
32
32
32
32
4
32
16
64
16
4
32
32
32
32
4
64
64
64
32
4
32
32
64
32
4
64
64
32
64
4
32
64
32
64
4
6e
6f
6 g
6h
6i
4
4
4
4
4
4
4
4
4
6j
32
64
2
64
64
2
64
64
2
64
64
2
64
64
2
64
64
2
32
64
2
64
64
2
64
64
16
E
Standard druga
a
Streptomycin sulphate for bacterial strains, and fluconazole for fungal strains were used as standard drugs.
spectrometers. The chemical shifts (δ) for protons were reported in
ppm downfield from TMS as the internal standard and the carbon
shifts were referenced to the 13C signal of CDCl3 at δ = 77.0 ppm.
Coupling constants (J) were expressed in Hz.Infrared spectra were
obtained with a Thermo Nicolet Nexus 670 spectrometer using KBr
discs. Melting points were measured on a BUCHI melting point ma-
chine in open capillary tubes. The UV-visible spectra were recorded
with a Varian Cary 500 spectrophotometer over the range 250–
700 nm using 1 cm path length cuvettes. Cyclic voltammetry (CV)
was performed with a conventional three electrode configuration
consisting of glassy carbon as a working electrode, platinum as an
auxiliary electrode and a saturated calomel electrode (SCE) as a
reference electrode. Cyclic voltammograms were recorded in pres-
ence of 0.1 M tetrabutylammonium perchlorate (TBAP) as the sup-
porting electrolyte at a scan rate of 100 mV s_1, using a CHI620
model electrochemical analyser at room temperature.
vent mixture to afford compound furnished the desired N-alkyl l
bromo isatin in good yields.
4.2. General procedure for the synthesis of compound (3)
To a stirred solution of N-alkyl bromo isatin (2) (1 mmol)
in DMF (10 mL), NaN3 (1.5 mmol) was added. The mixture was
stirred at reflux for about 3 h (monitored by TLC). Upon com-
pletion of reaction, the mixture was washed with water andex-
tracted with dichloromethane. The combined organic layers were
dried (Na2SO4) and filtered, concentrated in vacuum. The obtained
azides (3) were used without further purification.
4.3. General procedure for the synthesis of compound (4)
Compound (3) (1 mmol) along with NaOH (1.5 mmol) was dis-
solved in ethanol and later hydroxyl amine (1.5 mmol) was added
slowly. The reaction mixture was stirred at room temperature for
1 h (monitored by TLC). Upon completion of reaction, the mixture
was washed with water and extracted with ethyl acetate. The com-
bined organic layer was dried over Na2SO4 and the product was
obtained by the removal of the solvent under vacuum. It was pu-
rified by column chromatography on silica, using a hexane-ethyl
acetate (70:30) solvent mixture to afford compound furnished the
desired compound (4) in good yields.
4.1. General procedure for the synthesis of compound (2)
To
a stirred suspension of potassium carbonate (2.76 g,
20 mmol) in acetonitrile (10 ml), add isatin 1 (1.47 g, 10 mmol),
and stir at room temperature for 10 min followed by the addition
of 1,3 and 1,4-dibromoalkane (10 mmol) in acetonitrile at room
temperature for 2 h. After the completion of reaction, as evidenced
by TLC, K2CO3 was filtered off, and the solution was extracted with
ethyl acetate (50 mL). Acetonitrile was removed by rotary evapora-
tor and extracted with ethyl acetate. The combined organic layer
was dried over Na2SO4 and the product was obtained by the re-
moval of the solvent under vacuum. It was purified by column
chromatography on silica, using a hexane-ethyl acetate (80:20) sol-
4.4. General procedure for the synthesis of compound (5)
2,4-Thiazolidinedione (A) was prepared by literature method
[52] and was condensed with ferrocenecarboxaldehyde under Kno-
7

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
evenagel conditions to form ferrocenylidene 2,4-thiazolidinedione
(B) in the presence of piperidine as catalyst in dry ethanol. In the
next step, compound (B) was coupled with propargyl bromide in
the presence of K2CO3 in dry DMF under inert atmosphere at room
temperature for 16 h to obtain the intermediate alkyne (5) [53].
4.8. Compound 6(b)
According to the general procedure, the reaction of compound
(5) (351 mg, 1 mmol) and 1-(3-azidopropyl)−3-(hydroxyimino)
5-methylindolin-2-one (259 mg, 1 mmol) resulted in 6(b) as a red
solid. Yield, (488 mg, 80%) mp: 182–184 °C; 1H NMR (400 MHz,
CDCl3+DMSO, ppm): δ 12.93 (s, 1H, OH), 7.97(d, J = 22.7 Hz, 1H,
Ar-H), 7.85(s, 1H, =CH), 7.77 (s, 1H, triazole), 7.16 (d, J = 7.9 Hz,
4.5. General procedure for the preparation of 6(a-j)
–
1H, Ar-H), 6.70 (d, J = 8.0 Hz, 1H, Ar-H), 5.01 (s, 2H, N CH2),
4.57 (s, 4H, C5H4), 4.44 – 4.35 (m, 2H, triazole-NCH2), 4.21(s, 5H,
C5H5), 3.79 (t, J = 6.5 Hz, 2H, isatin-NCH2), 2.33 – 2.28 (m, 2H,
CH2), 1.35 – 1.17 (m, 3H, CH3). 13C NMR (75 MHz, CDCl3+DMSO,
Copper sulphate (0.05 mmol) and sodium ascorbate
(0.13 mmol)was added to a stirred solution of compound (5)
(1 mmol) and 1-(2-azidoalkyl)−3-(hydroxyimino) indolin-2-one
(4) (1 mmol) in THF:water (1:1) mixture. The reaction mixture was
allowed to stir at room temperature for 30 min. After completion
of reaction as evidenced by TLC, water (20 mL) was added and
the reaction mixture was extracted with ethyl acetate. The com-
bined organic layers were dried over anhydrous sodium sulphate,
concentrated under reduced pressure and purified via column
chromatography using 40:60 (hexane:EtOAc) mixture.
=
=
=
ppm): δ 167.4(C O), 165.0(C O), 164.4(C O), 156.0(isatin, 4°),
144.0(triazole, 4°), 141.6(=C), 136.7(triazole, 3°), 136.1(C6H5),
124.1(C6H5), 117.1(C6H5), 116.8(C6H5), 116.6(C6H5), 114.0(C6H5),
=
108.7(C CH), 76.3(C5H4), 72.2(C5H4), 70.6(C5H4), 70.0(C5H5),
–
55.9(CH3), 47.7(triazole,N CH2), 36.9(N CH2), 36.4(isatin, N CH2),
–
–
28.2(CH2). HRMS (ESI) Calcd. For (C29H26FeN6O4S) [M
+
H]
+= 611.11584; found: 611.11604; IR (KBr, νmax/ cm−1) = 3150,
3027, 2859, 1712, 1680, 1607, 1474, 1355, 1040, 895, 482. UV–
Vis (CH3CN): λmax[ε in M−1 cm−1] =332(6750), 501(1000) nm.
Anal. calcd for (C29H26FeN6O4S): C, 56.94; H, 4.25; N, 13.75;S,
5.24; found: C, 57.06; H, 4.31; N, 13.97; S, 4.99.
4.6. Procedure for the preparation of compounds (C) and (D)
2,4-Thiazolidinedione (B) was prepared by literature method
[53] and was condensed with aldehydes under Knoevenagel con-
ditions to form arylidene 2,4-Thiazolidinedione (C) in the presence
of piperidine as catalyst in dry ethanol. In the next step, compound
(C) was coupled with propargyl bromide in the presence of K2CO3
in dry acetone under inert atmosphere at reflux temperature for
4 h to obtain the intermediate alkyne (D) [54a,b].
4.9. Compound 6(c)
According to the general procedure, the reaction of compound
(5) (351 mg,
1
mmol) and1-(3-azidopropyl)−3-(hydroxyimino)
5-methoxyindolin-2-one (275 mg, 1 mmol) resulted in (6c) as
a red solid. Yield, (469 mg, 75%); mp: 158–160 °C; 1H NMR
(400 MHz, CDCl3+DMSO, ppm): δ 12.93 (s, 1H, OH), 7.84 (d,
J
= 21.6 Hz, 1H, Ar-H), 7.78 (s, 1H, =CH), 7.77 (s, 1H, tria-
zole), 6.91 (dd, J = 8.5, 2.6 Hz, 1H, Ar-H), 6.72 (d, J = 8.5 Hz,
4.7. General procedure for the preparation of compound (E)
–
1H, Ar-H), 5.02 (s, 2H, N CH2), 4.56 (s, 4H, C5H4), 4.40 (t,
J = 6.7 Hz, 2H, triazole-NCH2), 4.20 (s, 5H, C5H5), 3.80 (s, 3H,
OCH3), 3.78 (d, J = 6.8 Hz, 2H, isatin-NCH2), 2.35 – 2.28 (m,
Copper sulphate (0.05 mmol) and sodium ascorbate
(0.13 mmol) was added to a stirred solution of compound (D)
(1 mmol) and 1-(2-azidoalkyl)−3-(hydroxyimino) indolin-2-one
(4) (1 mmol) in THF:water (1:1) mixture. The reaction mixture was
allowed to stir at room temperature for 30 min. After completion
of reaction as evidenced by TLC, water (20 mL) was added and
the reaction mixture was extracted with ethyl acetate. The com-
bined organic layers were dried over anhydrous sodium sulphate,
concentrated under reduced pressure and purified via column
chromatography using 40:60 (hexane: EtOAc) mixture to obtain
compound (E) in good yield.
2H, CH2).13C NMR (101 MHz, CDCl3+DMSO, ppm): δ 167.4(C O),
=
=
=
165.0(C O), 164.4(C O), 156.0(isatin, 4°), 144.0(triazole, 4°),
141.6(=C), 136.7(triazole, 3°), 136.1(C6H5), 124.1(C6H5), 117.1(C6H5),
=
116.8(C6H5), 116.6(C6H5), 114.0(C6H5), 108.78(C CH), 76.3(C5H4),
72.2(C5H4), 70.6(C5H4), 70.0(C5H5), 55.9(OCH3), 47.7(triazole,
–
–
–
N CH2), 36.9(N CH2), 36.4(isatin, N CH2), 28.2(CH2). HRMS
(ESI) Calcd. For (C29H26FeN6O5S) [M+H] += 627.11076; found:
627.11150; IR (KBr, νmax
/
cm−1
)
=
3148, 3028, 2858, 1719,
1680, 1606, 1471, 1357, 1072, 898, 487. UV–Vis (CH3CN): λmax[ε
in M−1 cm−1
332(5774), 505 (838) nm. Anal. calcd for
]
=
According to the general procedure, the reaction of compound
(5) (351 mg, 1 mmol) and 1-(3-azidopropyl)−3-(hydroxyimino)
indolin-2-one (245 mg, 1 mmol) resulted in 6(a) as a red solid.
Yield, (464 mg, 78%); mp: 115–117 °C; 1H NMR (400 MHz, CDCl3,
ppm): δ 12.3 (s, 1H, OH), 8.13 (d, J = 7.3 Hz, 1H, Ar-H), 7.84 (s, 1H,
=CH), 7.78 (s, 1H, triazole), 7.37 (t, J = 7.6 Hz, 1H, Ar-H), 7.09 (t,
J = 7.6 Hz, 1H, Ar-H), 6.81 (d, J = 7.8 Hz, 1H, Ar-H), 5.02 (s, 2H,
(C29H26FeN6O5S): C, 55.49; H, 4.15; N, 13.39; S, 5.1; found: C,
55.36; H, 4.28; N, 13.77; S, 5.25.
4.10. Compound 6(d)
According to the general procedure, the reaction of compound
(5) (351 mg, 1 mmol) and 1-(3-azidopropyl)−3-(hydroxyimino) 5-
fluoroindolin-2-one (263 mg, 1 mmol) resulted in (6d) as a red
solid. Yield, (429 mg, 70%); mp: 172–174 °C; 1H NMR (300 MHz,
CDCl3+DMSO, ppm): δ 13.39 (s, 1H, OH), 7.96 (s, 1H, =CH), 7.82
(dt, J = 12.2, 6.1 Hz, 1H, Ar-H), 7.76 (s, 1H, triazole), 7.11 (td, J = 8.9,
2.5 Hz, 1H, Ar-H), 6.83 (dd, J = 8.5, 3.9 Hz, 1H, Ar-H), 4.94 (d,
–
N CH2), 4.56 (s, 4H, C5H4), 4.40 (t, J = 6.7 Hz, 2H, triazole-NCH2),
4.19 (d, J = 9.5 Hz, 5H, C5H5), 3.82 (t, J = 6.5 Hz, 2H, isatin-NCH2),
2.40 – 2.31 (m, 2H, CH2). 13C NMR (101 MHz, CDCl3, ppm): δ
=
=
=
167.4(C O), 165.0(C O), 164.5(C O), 143.7(isatin, 4°), 142.4(tria-
zole, 4°), 141.6(=C), 136.7(triazole, 3°), 131.7(C6H5), 127.8(C6H5),
=
124.1(C6H5), 123.1(C6H5), 116.8(C6H5), 116.0(C6H5), 108.2(C CH),
–
76.3(C5H4), 72.2(C5H4), 70.5(C5H4), 69.9(C5H5), 47.6(triazole,
J = 25.4 Hz, 2H, N CH2), 4.59 (s, 4H, C5H4), 4.43 (t, J = 6.7 Hz,
–
–
–
N CH2), 36.8(N CH2), 36.3(isatin, N CH2), 28.2(CH2). HRMS
(ESI) Calcd. For (C28H24FeN6O4S) [M + H] +=597.10019; found:
597.10062; IR (KBr, νmax/ cm−1)=3141, 3078, 2922, 1728, 1677,
1606, 1461, 1360, 1050, 877, 480; UV–Vis (CH3CN): λmax[ε in M−1
cm−1] =333(4454), 502(639) nm. Anal. calcd for (C28H24FeN6O4S):
C, 56.39; H, 4.06; N, 14.09; S, 5.36; found: C, 56.64; H, 4.26; N,
14.90; S, 5.06.
2H, triazole-NCH2), 4.15 (s, 5H, C5H5), 3.81 (t, J = 6.5 Hz, 2H,
isatin-NCH2), 2.41
–
2.20 (m, 2H, CH2). 13C NMR (75 MHz,
=
=
=
CDCl3+DMSO, ppm):
δ 166.2(C O), 163.9(C O), 163.0(C O),
156.1(isatin, 4°), 140.5(triazole, 4°), 137.7(=C), 135.5(triazole, 3°),
123.1(C6H5), 117.1(C6H5), 116.7(C6H5), 115.8(C6H5), 114.2(C6H5),
=
113.9(C6H5), 108.2(C CH), 75.3(C5H4), 71.3(C5H4), 69.6(C5H4),
–
–
–
69.0(C5H5), 46.6(triazoleN CH2), 36.0(N CH2), 35.4(isatin, N CH2),
8

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
+
27.1(CH2). HRMS (ESI) Calcd. For (C28H23FFeN6O4S) [M+H]
=
2H, triazole-NCH2), 4.18 (s, 5H, C5H5), 3.77 (t, J = 6.7 Hz, 2H,
isatin-NCH2), 2.33 (s, 3H, CH3), 1.94 (dd, J = 14.8, 7.2 Hz, 2H,
CH2), 1.70 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3+DMSO,
615.09077; found: 615.09095; IR (KBr, νmax
/
cm−1
)
=3152,
3022, 2923, 1719, 1677, 1605, 1470, 1330, 1073, 876, 486. UV–
Vis (CH3CN): λmax[ε in M−1 cm−1] =334(6718), 509 (968) nm..
Anal. calcd for (C28H23FFeN6O4S): C, 54.63; H, 3.74; N, 13.66; S,
5.2; found: C, 54.83; H, 3.87; N, 13.96; S, 4.98.
=
=
=
ppm): δ 172.0(C O), 169.7(C O), 168.9(C O), 148.7(isatin, 4°),
146.3(triazole, 4°), 145.3(=C), 141.3(triazole, 3°), 137.0(C6H5),
136.8(C6H5), 133.1(C6H5), 128.2(C6H5), 121.5(C6H5), 120.7(C6H5),
=
112.9(C CH), 81.1(C5H4), 77.0(C5H4), 75.3(C5H4), 74.7(C5H5),
–
–
54.2(CH3), 43.4(triazoleN CH2), 41.1(N CH2), 34.3(isatin, N CH2),
–
4.11. Compound 6(e)
32.1(CH2), 25.7(CH2). HRMS (ESI) Calcd. For (C30H28FeN6O4S)
[M+H] += 625.13149; found: 625.13432; IR (KBr, νmax/ cm−1
)
According to the general procedure, the reaction of compound
=3417, 3143, 2923, 1724, 1677, 1606, 1475, 1363, 1060, 817, 488.
UV–Vis (CH3CN): λmax[ε in M−1 cm−1] = 333(3906), 504 (625)
nm. Anal. calcd for (C30H28FeN6O4S): C, 57.64; H, 4.48; N, 13.44;
S, 5.12; found: C, 57.06; H, 4.39; N, 13.67, S, 5.35.
(5) (351 mg, 1 mmol) and 1-(3-azidopropyl)−3-(hydroxyimino)
5-bromoindolin-2-one (323 mg,
1 mmol) resulted in 6(e) as
a red solid. Yield, (532 mg, 79%); mp: 162–164 °C; 1H NMR
(400 MHz, CDCl3+DMSO, ppm): δ 13.35 (s, 1H, OH), 8.27 (s,
1H, =CH), 7.86 (d, J = 10.7 Hz, 1H, Ar-H), 7.78 (s, 1H, tria-
zole), 7.57
–
7.43 (m, 1H, Ar-H), 6.83 – 6.65 (m, 1H, Ar-H),
–
5.01 (s, 2H, N CH2), 4.51 (d, J = 51.9 Hz, 4H, C5H4), 4.49 –
4.14. Compound 6(h)
4.32 (m, 2H, triazole-NCH2), 4.17 (s, 5H, C5H5), 3.80 (s, 2H,
isatin-NCH2), 2.39
–
2.25 (m, 2H, CH2). 13C NMR (75 MHz,
According to the general procedure, the reaction of compound
=
=
=
CDCl3+DMSO, ppm):
δ
167.6(C O), 165.2(C O), 164.1(C O),
(5) (351 mg,
1
mmol) and 1-(3-azidobutyl)−3-(hydroxyimino)
142.9(isatin, 4°), 141.8(triazole, 4°), 139.3(=C), 136.9(triazole, 3°),
5-chloroindolin-2-one (293 mg, 1 mmol) resulted in 6(h) as a red
solid. Yield, (528 mg, 82%);mp: 150–152 °C;1H NMR (400 MHz,
CDCl3+DMSO, ppm): δ 13.25 (s, 1H, OH), 8.11 (d, J = 2.1 Hz, 1H,
Ar-H), 7.71 (s, 1H, =CH), 7.73 (s, 1H, triazole), 7.34 (dd, J = 8.4,
2.2 Hz, 1H, Ar-H), 6.78 (d, J = 8.4 Hz, 1H, Ar-H), 4.98 (s, 2H,
134.3(C6H5), 130.6(C6H5), 124.2(C6H5), 117.5(C6H5), 115.7(C6H5),
=
114.1(C6H5), 109.9(C CH), 76.4(C5H4), 72.3(C5H4), 70.7(C5H4),
–
–
–
70.1(C5H5), 47.7(triazole, N CH2), 37.1(N CH2), 29.7(isatin, N CH2),
+
22.7(CH2). HRMS (ESI) Calcd. For (C28H23BrFeN6O4S) [M+H]
=
cm−1
)
=3413,
N CH2), 4.57 (s, 4H, C5H4), 4.47 – 4.35 (m, 2H, triazole-NCH2),
–
677.0109077; found: 677.01595; IR (KBr, νmax
/
3148, 2925, 1725, 1679, 1602, 1463, 1357, 1045, 886, 488. UV–
Vis (CH3CN): λmax[ε in M−1 cm−1] =334(8448), 505(1068) in nm..
Anal. calcd for (C28H23BrFeN6O4S): C, 49.63; H, 3.40; N, 12.41; S,
4.73; found: C, 49.80; H, 3.48; N, 12.54; S, 5.01.
4.21 (s, 5H, C5H5), 3.77 (t, J = 6.8 Hz, 2H, isatin-NCH2), 1.95 (dd,
J = 14.6, 7.2 Hz, 2H, CH2), 1.69 (m, 2H, CH2). 13C NMR (101 MHz,
=
=
=
CDCl3+DMSO, ppm):
δ 167.3(C O), 164.9(C O), 163.8(C O),
142.9(isatin, 4°), 141.6(triazole, 4°), 141.1(=C), 136.6(tria-
zole, 3°), 131.1(C6H5), 130.9(C6H5), 128.7(C6H5), 127.9(C6H5),
=
4.12. Compound 6(f)
127.6(C6H5), 123.3(C6H5), 116.8(C6H5), 116.7(C6H5), 109.3(C CH),
76.2(C5H4), 72.1(C5H4), 70.5(C5H4), 69.9(C5H5), 49.3(triazole,
–
–
–
According to the general procedure, the reaction of compound
N CH2), 38.7(N CH2), 36.3(isatin, N CH2), 27.2(CH2), 24.2(CH2).
(5) (351 mg,
1
mmol) and 1-(3-azidobutyl)−3-(hydroxyimino)
HRMS (ESI) Calcd. For (C29H25ClFeN6O4S) [M+H] += 645.07687;
indolin-2-one (259 mg, 1 mmol) resulted in 6(f) as a red solid.
Yield, (475 mg, 78%); mp: 171–173 °C; 1H NMR (400 MHz, CDCl3,
ppm): δ 12.93 (s, 1H, OH), 8.11 (d, J = 7.5 Hz, 1H, Ar-H), 7.77
(s, 1H, =CH), 7.67 (s, 1H, triazole), 7.36 (t, J = 7.8 Hz, 1H, Ar-H),
7.06 (t, J = 7.6 Hz, 1H, Ar-H), 6.83 (d, J = 7.9 Hz, 1H, Ar-H),
found: 645.07939; IR (KBr, νmax
1728, 1678, 1605, 1462, 1371, 1059, 817, 488. UV–Vis (CH3CN):
/
cm−1
)
=3417, 3144, 2925,
λ
max[ε in M−1 cm−1] = 334(6258), 505 (870) nm. Anal. calcd for
(C29H25ClFeN6O4S): C, 53.95; H, 3.87; N, 13.02; S, 4.96; found: C,
54.01; H, 3.91; N, 13.13; S, 4.23.
–
4.98 (s, 2H, N CH2), 4.57 (s, 4H, C5H4), 4.41 (t, J = 7.0 Hz,
2H, triazole-NCH2), 4.19 (s, 5H, C5H5), 3.79 (t, J = 6.8 Hz, 2H,
isatin-NCH2), 1.96 (dd,
J
=
14.8, 7.3 Hz, 2H, CH2), 1.73 (dt,
4.15. Compound 6(i)
J = 13.7, 6.8 Hz, 2H, CH2). 13C NMR (101 MHz, CDCl3, ppm): δ
=
=
=
167.6(C O), 165.2(C O) 164.2(C O), 144.4(isatin, 4°), 143.2(tria-
According to the general procedure, the reaction of compound
zole, 4°), 141.8(=C), 137.0(triazole, 3°), 132.4(C6H5), 128.3(C6H5),
(5) (351 mg,
1
mmol) and 1-(3-azidobutyl)−3-(hydroxyimino)
=
123.6(C6H5), 123.3(C6H5), 116.8(C6H5), 115.7(C6H5), 108.6(C CH),
5-flouroindolin-2-one (277 mg, 1 mmol) resulted in 6(i) as a red
solid. Yield, (477 mg, 76%);mp: 165–167 °C;1H NMR (300 MHz,
CDCl3+DMSO, ppm): δ 13.31 (s, 1H, OH), 7.82 (dt, J = 8.4, 4.2 Hz,
1H, Ar-H), 7.76 (s, 1H, =CH), 7.75(s, 1H, triazole), 7.09 (tt, J = 16.3,
8.2 Hz, 1H, Ar-H), 6.80 (dt, J = 25.3, 12.7 Hz, 1H, Ar-H), 5.06
76.4(C5H4), 72.2(C5H4), 70.7(C5H4), 70.0(C5H5), 49.5(triazole,
–
–
–
N CH2), 38.8(N CH2), 36.4(isatin, N CH2), 27.3(CH2), 24.1 (CH2).
+
HRMS (ESI) Calcd. For (C29H26FeN6O4S) [M+H]
found: 611.11849; IR (KBr, νmax
cm−1
1726, 1679, 1605, 1462, 1363, 1015, 823, 495. UV–Vis (CH3CN):
=
611.11584;
/
)
=3418, 3143, 2924,
–
– 4.90 (m, 2H, N CH2), 4.59 (s, 4H, C5H4), 4.42 (t, J = 6.9 Hz,
λ
max[ε in M−1 cm−1] =334(5906), 510 (1062) nm. Anal. calcd for
2H, triazole-NCH2), 4.22 (s, 5H, C5H5), 3.78 (t,
J
=
6.7 Hz,
(C29H26FeN6O4S): C, 56.94; H, 4.25; N, 13.75; S, 5.24; found: C,
57.06; H, 4.39; N, 13.67; S, 5.35.
2H, isatin-NCH2), 1.95 (dd, J = 14.8, 7.3 Hz, 2H, CH2), 1.77 –
1.62 (m, 2H, CH2). 13C NMR (101 MHz, CDCl3+DMSO, ppm): δ
=
=
=
166.5(C O), 164.1(C O), 163.1(C O), 142.6(isatin, 4°), 140.8(tria-
4.13. Compound 6(g)
zole, 4°), 138.0(=C), 135.8(triazole, 3°), 122.7(C6H5), 117.2(C6H5),
=
116.9(C6H5), 115.9(C6H5), 114.4(C6H5), 114.2(C6H5), 108.3(C CH),
According to the general procedure, the reaction of compound
75.5(C5H4), 71.5(C5H4), 69.8(C5H4), 69.2(C5H5), 48.6(triazole,
–
–
–
(5) (351 mg,
5-methylindolin-2-one (273 mg,
red solid. Yield, (499 mg, 80%); mp: 146–148 °C;1H NMR
1
mmol) and 1-(3-azidobutyl)−3-(hydroxyimino)
N CH2), 38.0(N CH2), 35.6(isatin, N CH2), 28.7(CH2), 23.4(CH2).
1
mmol) resulted in 6(g) as
HRMS (ESI) Calcd. For (C29H25FFeN6O4S) [M+H] += 629.10642;
a
found: 629.10911; IR (KBr, νmax
1726, 1677, 1605, 1471, 1370, 1064, 817, 484. UV–Vis (CH3CN):
/
cm−1
)
=3417, 3140, 2923,
(300 MHz, CDCl3+DMSO, ppm): δ 12.98 (s, 1H, OH), 7.93 (s,
1H, =CH), 7.76 (s, 1H, triazole), 7.75 (s, 1H, Ar-H), 7.19 (dd,
J = 14.0, 5.2 Hz, 1H, Ar-H), 6.73 (t, J = 9.3 Hz, 1H, Ar-H), 5.04
λ
max[ε in M−1 cm−1] = 332(5000), 506 (741) nm. Anal. calcd for
(C29H25FFeN6O4S): C, 55.36; H, 3.97; N, 13.35; S, 5.08; found: C,
55.42; H, 4.01; N, 13.47; S, 5.26.
–
– 4.90 (m, 2H, N CH2), 4.58 (s, 4H, C5H4), 4.40 (t, J = 6.9 Hz,
9

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
4.16. Compound 6(j)
J
=
9.1 Hz, 2H, Ar-H), 7.35 (dd,
J
=
8.8, 3.0 Hz, 1H, Ar-
H), 6.86 (d, J = 9.1 Hz, 2H, Ar-H), 4.18 (d, J = 14.9 Hz, 2H,
CH2), 3.35 (s, 6H, 2–OCH3), 3.03 (d, J = 4.8 Hz, 2H, CH2), 2.51
According to the general procedure, the reaction of compound
(5) (351 mg,
1
mmol) and 1-(3-azidobutyl)−3-(hydroxyimino)
(dd, J = 3.6, 1.8 Hz, 2H, CH2), 1.62 – 1.59 (m, 2H, CH2).13
C
=
=
5-bromoindolin-2-one (337 mg, 1 mmol) resulted in 6(j) as a red
solid. Yield, (429 mg, 77%); mp: 168–170 °C; 1H NMR (300 MHz,
CDCl3+DMSO, ppm): δ 13.10 (s, 1H, OH), 8.17 (t, J = 19.4 Hz,
1H, Ar-H), 7.73 (s, 1H, =CH), 7.67 (s, 1H, triazole), 7.45 (dd,
J = 8.4, 2.0 Hz, 1H, Ar-H), 6.76 (dd, J = 26.0, 8.1 Hz, 1H, Ar-H),
NMR (101 MHz, CDCl3, ppm) δ 167.58 (C O), 165.88 (C O),
162.30(C6H4), 152.94(C6H4), 149.37(C6H4), 142.09 (=CH), 134.56,
132.64 (Tr-4°C), 128.43(C6H5), 124.81(C6H5), 124.27 (C6H4), 123.56
(=CH), 121.96(C6H5), 118.44(C6H5), 112.45(C6H4), 111.43(C6H5),
108.63(C6H5), 56.10(OCH3), 56.00 (OCH3), 47.68(CH2), 37.11(CH2),
–
–
4.95 (s, 2H, N CH2), 4.54 (s, 4H, C5H4), 4.37 (t, J = 6.9 Hz,
31.96(CH2), 29.73 (N CH2). Mass Calcd. For (C26H24N6O6S) [M]
2H, triazole-NCH2), 4.18 (s, 5H, C5H5), 3.74 (t,
J
=
6.8 Hz,
+=548.57; found: 548.90. Anal Calcd for (C26H24O6N6S): C, 56.87;
2H, isatin-NCH2), 1.98 – 1.86 (m, 2H, CH2), 1.67 (dd, J = 14.7,
H, 4.37; N. 15.31; S, 5.83; found: C, 57.15; H, 5.02; N, 14.97; S, 5.42.
7.1 Hz, 2H, CH2). 13C NMR (101 MHz, CDCl3+DMSO, ppm): δ
=
=
=
167.4(C O), 165.0(C O), 163.7(C O), 142.8(isatin, 4°), 141.7(tria-
5. Culture and maintenance of test microorganisms for
antimicrobial activity
zole, 4°), 141.5(=C), 136.7(triazole, 3°), 134.0(C6H5), 130.3(C6H5),
=
123.3(C6H5), 117.3(C6H5), 116.7(C6H5), 115.3(C6H5), 109.7(C CH),
76.3(C5H4), 72.2(C5H4), 70.5(C5H4), 69.9(C5H5), 49.3(triazole,
Pure cultures of selected bacteria and fungi strains were ob-
tained from the Microbial Type Culture Collection and Gene Bank
(MTCC), Institute of Microbial Technology (IMTECH), Chandigarh.
The bacterial cultures were maintained on nutrient broth while
fungal strains were on yeast peptone dextrose broth (YPD). These
microbial strains were subcultured regularly on their respective
media and stored at 4 °C till further use.
–
–
–
N CH2), 38.7(N CH2), 36.3(isatin, N CH2), 27.2(C+H2), 24.2(CH2).
HRMS (ESI) Calcd. For (C29H25BrFeN6O4S) [M]
=
689.02636;
found: 689.02694; IR (KBr, νmax
1728, 1677, 1604, 1463, 1371, 1051, 817, 488. UV–Vis (CH3CN):
/
cm−1
)
=3421, 3146, 2925,
λ
max[ε in M−1 cm−1] =333(7931), 513 (1103) nm. Anal. calcd for
(C29H25BrFeN6O4S): C, 50.50; H, 3.63; N, 12.19; S, 5.09; found: C,
51.03; H, 3.56; N, 12.49, S, 4.86.
5.1. In vitro antibacterial and antifungal activity
4.17. Compound (C)
All the synthesized novel triazole conjugates (6(a-j)) com-
pounds were evaluated for their in vitro antimicrobial ac-
tivity against four Gram-positive bacterial strains(B.subtillis,
B.megaterium, M.smegmatis, K. pneumoniae) four Gram-negative
bacterial strains (E.coli, S. typhi, P.putida, P. arguinos and two fungal
strains (C.albicans, A. oryzae). The assay was performed using the
agar well diffusion method. In brief, Mueller-Hinton agar (MHA)
medium is prepared, autoclaved and poured in a sterile Petriplates
According to the general procedure, the reaction of compound
(A) (167 mg, 1 mmol) and 2,4-Thiazolidinedione (B) (117 mg,
1 mmol) resulted in compound (C) as a yellow solid. 1H NMR
(500 MHz, CDCl3, ppm) δ 8.80 (s, 1H, NH), 7.74 (s, 1H, =CH), 7.07
(dd, J = 8.5, 1.9 Hz, 1H, Ar-H), 6.91 (dd, J = 18.2, 5.2 Hz, 2H, Ar-H),
3.88 (s, 3H, OCH3), 3.87 (s, 3H, OCH3).13C NMR (101 MHz, CDCl3,
=
=
ppm)
δ
134.66(C6H4),
167.26(C O), 166.74(C O), 151.46(C6H4), 149.39(=C),
under sterile conditions. After solidification, 50 μL (106 CFU mL−1
)
125.87(C6H5), 124.93(C6H4), 119.47(C6H5),
of test bacterial culture were inoculated and spread uniformly by
sterile cotton swabs and 8 mm wells were made on agar plate
using sterile cork borer. A 100 μg mL−1 stock solution of test
compounds and standard drugs streptomycin sulphate for bacterial
strains and fluconazole as a standard for fungal strains were pre-
pared using DMSO (Dimethyl sulfoxide) as a solvent. DMSO was
used as negative control. 100 μL of the test samples, streptomycin
and DMSO were loaded individually in separate wells. The plates
were incubated at 37 °C for 18 h and the zone of inhibition
measured by using calibrated scale and expressed in mm. All the
experiments were carried out in triplicates and mean values were
considered for data representation [55].
112.42(C6H5), 111.43(C6H5), 56.12(OCH3), 55.99(OCH3).Mass Calcd.
For (C12H11 NO4S)[M] +=265.04;found: 265.90. Anal Calcd for
(C12H11 O4NS): C, 54.33; H, 4.18; N. 5.26; S, 12.07; found: C, 55.15;
H, 4.52; N, 5.62; S, 11.92.
4.18. Compound (D)
According to the general procedure, the reaction of compound
(C) (265 mg, 1 mmol) and in compound (D) as a yellow solid.1H
NMR (400 MHz, CDCl3, ppm) δ 7.89 (s, 1H, =CH), 7.15 (dd,
J = 8.4, 2.1 Hz, 1H, Ar-H), 7.02 – 6.94 (m, 2H, Ar-H), 4.49 (dd,
J = 12.3, 2.5 Hz, 2H, -CH2), 3.95 (s, 3H, OCH3), 3.94 (s, 3H, OCH3),
2.27 (q, J = 2.7 Hz, 1H, Acetylic). 13C NMR (101 MHz, CDCl3,
Minimum inhibitory concentration (MIC) is defined as the low-
est concentration able to inhibit any visible bacterial growth. The
assays were performed by broth dilution techniques. The different
dilutions (0.5,1, 2, 4, 8, 16, 32,64 μg mL−1 in DMSO) of compounds,
streptomycin sulphate and fluconazole as standards as well as pos-
itive controls were prepared and transferred to the test bacterial
and fungal cultures which were grown in Mueller Hinton broth.
The tubes were incubated in shaking incubator for 12 h at 37 °C
and subsequently checked for the growth of bacteria and fungi by
taking absorbence at 560 nm. The test organisms are then added
to the dilutions of the synthesized and incubated for growth.
=
=
ppm) δ 166.98(C O), 165.23(C O), 151.45 (C6H4), 149.40 (C6H5),
134.85(=C), 125.98(C6H4), 124.90(C6H4), 118.13 (=C), 112.43(C=),
≡
≡
111.44(C6H5), 76.20 ( C), 72.18 ( C), 56.13 (OCH3), 56.00 (OCH3),
30.65(CH2).Mass Calcd. For (C15H13NO4S) [M] +=303.33; found:
303.90. Anal Calcd for (C15H13O4NS): C, 59.40; H, 4.32; N. 4.62%;
S, 10.56; found: C, 60.06; H, 4.00%; N, 5.08%, S, 10.91.
4.19. Compound (E)
According to the general procedure, the reaction of compound
(D) (303 mg, 1 mmol) and 1-(3-azidopropyl)−3-(hydroxyimino)
indolin-2-one (245 mg, 1 mmol) resulted in (E) as a yellow solid.
1H NMR (400 MHz, DMSO, ppm) δ 10.16 (s, 1H, OH)),
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
8.37 (s, 1H, =CH), 8.16 (s, 1H, Tr-H), 8.02 (d,
J
=
8.8 Hz,
1H, Ar-H), 7.92 (dd, J 8.8, 2.0 Hz, 1H, Ar-H), 7.42 (d,
=
10

S. Yagnam, R. Trivedi, S. Krishna et al.
Journal of Organometallic Chemistry 937 (2021) 121716
The authors declare the following financial interests/personal
relationships which may be considered as potential competing in-
terests.
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Acknowledgments
This work was financially supported by the CSIR-IICT (in-house
project MLP-0007) and DST (EMR/2016/006410). Swetha Yagnam is
grateful to the University Grants Commission (UGC), New Delhi for
the award of a research fellowship. We thank Director, CSIR-IICT
(Ms. No. IICT/Pubs./2020/204) for providing all the required facili-
ties to carry out the work.
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Supplementary materials
Supplementary material associated with this article can be
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