M. Lavanya et al.
Inorganica Chimica Acta 524 (2021) 120440
molecules, such as triapine, are under Phase II clinical trials for cancer
chemotherapy [7]. The nature of the heteroaromatic ring and the type of
substituents attached to the heterocyclic ring of thiosemicarbazones
strongly reflect their biological activities [8].
thiosemicarbazide was performed as follows; an ethanolic solution (15
mL) of equimolar amounts of thiosemicarbazide (10 mmol), 4′-methyl-
3-thiosemicarbazide (5 mmol), and 4′-phenyl-3-thiosemicarbazide (5
mmol) was added to an ethanolic (99%) solution of 5′-methyl-2-thio-
phenecarboxaldehyde (0.01–0.005 mol). Subsequently, 2 mL of acetic
acid was added to the reaction mixtures as a catalyst and the entire
contents of the flasks were heated under refluxed conditions for about 3
h. The obtained precipitates were filtered, washed with cold ethanol,
then purified by recrystallization. The yellow to brown crystalline solids
obtained were filtered and dried in a vacuum.
Therefore, it is clearly understood that the heterocyclic thio-
semicarbazones have attracted considerable attention because of their
appreciable repeatability, highly beneficial pharmacological properties,
and different modes of binding [9]. In addition, most thio-
semicarbazones exhibit other biological properties, including antitumor
[10-12], antibacterial [13] and antifungal [14-16] activities. Alongside
the transition metal complexes of these ligands are also being used for a
broad spectrum of medicinal applications towards colon cancer [17,18].
The structural similarity of phenylthiosemicarbazones with phenyl-
thioureas with an additional imine group lying adjacent to the thiourea
anion binding site has made them function better pH-switchable anion
transporters compared to phenylthioureas [19] and squaramides
[20,21]. We also demonstrated that the class of thiosemicarbazone
shows the pH switchable transport of anions at pH 4.0 and could be used
for the targeted anion efflux from the acidic lysosomal vesicles in the
cells [22]. The electroactive thiophene ring on thiosemicarbazone
complexes of ruthenium assisted in developing a new biosensor for the
determination of glucose [23]. Thus, it is very imperative to design and
synthesis of novel thiophene thiosemicarbazones and their metal(II)
complex derivatives for their versatile applications in biology, analytical
chemistry, and material science.
2.2.1. 5′-methyl-2-thiophene thiosemicarbazone (Httsc1)/(1)
5′-methyl-2-thiophenecarboxaldehyde (10 mmol, 1.261 g) and thi-
osemicarbazide (10 mmol, 0.911 g) was added to the ethanolic solution.
Subsequently, 2 mL of acetic acid was added during reflux. Yield: 1.25
g, (63.1%), Yellow colored solid. M.p: 170–172 ◦C, Anal. Calc. for
C7H9N3S2 (%): C, 42.19; H, 4.55; N, 21.09; S, 32.17, M.Wt: 199.0238;
FT-IR (KBr, ʋ, cm¡1): 1589 (C N), 819 (C S), 1034 (N N). UV–Vi-
–
–
–
–
–
sible (acetonitrile): λmax, nm; 250 (
π
→
π
), 336 (n →
π
*). 1H NMR (400
MHz, CDCl3, δ, ppm): 2.42 (s, 3H, thiophene attached CH3), 6.42 (s, 1H,
thiophene-H), 6.63–6.63 (t, J = 0.8, 1H, thiophene-H), 7.01–7.02 (t, J =
3.2, 2H, NH2), 7.97 (s, 1H, HC = N), 10.02 (s, 1H, NH). 13C NMR (100
MHz, CDCl3, δ, ppm): 14.21 (thiophene attached CH3 carbon), 126.21
–
(C N), 131.95, 135.49, 139.00, 144.55 (thiophene carbons), 177.59
–
–
(C S).
–
Herein, we designed and synthesized substituted thiophene thio-
semicarbazones and their metal(II) complexes. These complexes were
rationally investigated its structural and physicochemical characteriza-
tions by using different spectroscopic techniques. Most importantly, the
metal complexes are further tested for their in vitro anticancer activity
against different types of cell lines.
2.2.2. 5′-methyl-2-thiophene-N(4)-methylthiosemicarbazone (Httsc2)/(2)
5′-methyl-2-thiophenecarboxaldehyde (5 mmol, 0.630 g) and 4-
methyl-3-thiosemicarbazide (5 mmol, 0.525 g), was added to the etha-
nolic solution. Subsequently 2 mL of acetic acid was added. Yield: 1.20
g, (87%), pale brown colored solid, M.p: 240–242 ◦C, Anal. Calc. for
C6H11N3S2 (%): C, 45.04; H, 5.20; N, 19.70; S, 30.06. M.Wt: 213.0394;
–
–
–
–
–
S), 1029 (N N); UV–Visible (acetoni-
2. Experimental section
FT-IR: 1592 (C
N), 821 (C
), 335 (n →
trile): λmax, nm; 245 (
π
→
π
π
*). 1H NMR (400 MHz, CDCl3,
2.1. Materials and methods
δ, ppm): 2.42 (s, 3H, thiophene attached CH3), 3.16 (d, J = 4.8 Hz, 3H),
6.63–6.64 (d, J = 3.2 Hz, 1H, thiophene-H), 6.98–6.99 (d, J = 3.2 Hz,
1H, thiophene-H), 7.27 (s, 1H, terminal NH), 7.85 (s, 1H, HC = N), 9.67
(s, 1H, NH). 13C NMR (100 MHz, CDCl3, δ, ppm): 15.79 (thiophene
attached CH3 carbon), 31.6 (terminal CH3 carbon), 126.14, 131.28,
5′-Methyl-2-thiophenecarboxaldehyde,
thiosemicarbazide,
4-
methyl-3-thiosemicarbazide, 4-phenyl-3-thiosemicarbazide, copper(II)
sulfate, palladium(II) chloride and zinc(II) acetate were purchased from
Sigma Aldrich. All the solvents used in this study were obtained from
commercial sources and were used without any further purification. The
Fourier transform infrared (FT-IR, Nicolet 380) spectra of the com-
pounds were recorded in KBr pellets at room temperature. Experimental
absorption studies were carried out using a Shimadzu UV-1800 double
beam spectrophotometer. The compounds were confirmed preliminarily
by nuclear magnetic resonance spectroscopy (NMR, JEOL resonance
400 MHz NMR spectrometer) at the DST Purse Centre, Sri Venkateswara
University, Tirupati. X-ray diffraction (XRD, Bruker APEX 2 X-ray
(three-circle)) was used for crystal screening, unit cell determination,
and data collection. The X-ray radiation employed was generated from a
Mo sealed X-ray tube (Kα = 0.70173 Å with a potential of 40 kV and a
current of 40 mA) fitted with a graphite monochromator in parallel
mode (175 mm collimator with 0.5 mm pinholes). The data frames were
taken at widths of 0.5◦ 2θ. All non-hydrogen atoms were refined with the
anisotropic thermal parameters. The structure was refined (weighted
least-squares refinement on F2) to convergence [24,25]. Olex2 was used
for the final data presentation and structure plots [26]. The Electron
paramagnetic spectra of copper(II) complexes are recorded by using the
Bruker-ER073 instrument as polycrystalline samples.
–
135.79, 137.39 (thiophene carbons), 143.96 (C N), 177.79 (C S).
–
–
–
2.2.3. 5′-methyl-2-thiophene-N(4)-phenylthiosemicarbazone (Httsc3)/(3)
5′-methyl-2-thiophenecarboxaldehyde (5 mmol, 0.630 g) and 4-
phenyl-3-thiosemicarbazide (5 mmol, 0.418 g), was added to the etha-
nolic solution. Subsequently, 2 mL of acetic acid was added. Yield: 0.80
g, (80%), Brown colored solid, M.p: 152–154 ◦C. Anal. Calc. for
C
13H13N3S2 (%): C, 56.70; H, 4.76; N, 15.26; S, 23.28. M.Wt: 275.0551;
–
–
–
–
–
S), 1025 (N N), UV–Visible (acetoni-
FT-IR: 1527 (C
N), 802 (C
trile): λmax, nm; 264 (
π
→
π
), 344 (n →
π
*). 1H NMR (400 MHz, CDCl3,
δ, ppm): 2.48 (s, 3H thiophene attached CH3 carbon), 6.70–7.08 (m, 2H,
thiophene-H), 7.25–7.43 (m, 3H, aromatic-H), 7.64 (d, J = 7.6 Hz, 2H,
–
–
–
aromatic-H), 8.11 (s, 1H, C N), 9.08 (s, 1H, N H), 11.00 (s, 1H, NH).
13C NMR (100 MHz, CDCl3, δ, ppm): 15.92 (thiophene attached CH3
carbon), 124.8, 126.3, 126.3, 128.9 (aromatic), 135.8, 137.9, 138.4,
–
144.4 (thiophene) 132.0 (C N), 175.0 (C S).
–
–
–
2.2.4. Synthesis of metal(II) complexes
2.2.4.1. Bis(5′-methyl-2-thiophenethiosemicarbazonato)(diaqua)copper
(II), [Cu(ttsc1)2Cl2]/(4). To a hot solution of the free ligand 1 (0.59
mmol, 0.117 g) in ethanol, 10 mL of aqueous Cu(SO4)∙5H2O solution
(0.18 mol, 0.045 g) was added slowly under stirring. After refluxing for
24 h, the reaction resulted in the formation of a pale yellow colored
solution. The progress of the reaction was monitored by TLC using
EtOAc:Hexane (7:3) mixture as eluent. A yellow colored solid was
2.2. Synthesis
The general procedure for the synthesis of 5′-methyl-2-thio-
phenecarboxaldehyde-N(4)-un/substituted thiosemicarbazones (1–3) is
a slight modification of our previous study [27]. The condensation of 5′-
methyl-2-thiophenecarboxaldehyde
with
N(4)-un/substituted
2