Facile synthesis, spectral studies, DFT calculations and biological activities of novel NI (II), CU (II), and PD (II) complexes of thiadiazole analogs

Article abstract of DOI:10.22159/ijpps.2017v9i4.17130

Objective: A facile synthesis of some novel Schiff base derivatives of 2-substituted-5-amino-thiadiazoles along with their Ni (II), Cu (II), and Pd (II) complexes were achieved by sonication and the conventional method. In addition to establish the structure by DFT studies and to explore antimicrobial and anticancer activities of these novel compounds. Methods: The precursor 2-substituted-5-amino-thiadiazoles (T1-T3), target ligands and their metal complexes were synthesized by ultrasonication and conventional means. The isolated products were thoroughly characterized by physical and spectroscopic techniques including¹H-NMR,¹³C-NMR and IR spectroscopy. All characterized compounds were screened for antimicrobial activities using well diffusion method, and MTT assay was performed for cytotoxicity. Results: All novel compounds were synthesized by a green route i.e. ultra sonication and a noticeable improvement in yield with shorter reaction time than the conventional method were observed. The octahedral geometry was proposed for Ni (II)/Cu (II) complexes whereas square planar for Pd (II) complexes on the basis of the spectral techniques which were supported by DFT analysis by Gaussian03. On the analysis of antimicrobial activities, the compound T7 and T10 showed maximum antibacterial and antifungal activities respectively. However, compounds T25, T37, T31 found to be a potential cytotoxic compound with IC₅₀ value 0.469, 0.865 and 1.131 μM respectively. Conclusion: Analysis of synthetic protocol, it could be concluded that ultra-sonication is the better method to synthesize these potential biological active moiety. On the whole Cu (II) and Ni (II) complexes showed promising activity towards all microorganisms while Pd (II) complex emerged an excellent moiety in carcinoma cell line.

Full text of DOI:10.22159/ijpps.2017v9i4.17130

International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 9, Issue 4, 2017
Original Article
FACILE SYNTHESIS, SPECTRAL STUDIES, DFT CALCULATIONS AND BIOLOGICAL ACTIVITIES
OF NOVEL NI (II), CU (II), AND PD (II) COMPLEXES OF THIADIAZOLE ANALOGS
a
b
b
a*
PRIYANKA BHATT , S. DEEPTHI , CH. RAVI SHANKAR KUMAR , ANJALI JHA
a
b
Department of Chemistry, Department of Physics, GIS, GITAM University, Rushikonda, Visakhapatnam 530045, India
Email: anjalimanishjha@yahoo.com
Received: 17 Jan 2017 Revised and Accepted: 27 Feb 2017
ABSTRACT
Objective: A facile synthesis of some novel Schiff base derivatives of 2-substituted-5-amino-thiadiazoles along with their Ni (II), Cu (II), and Pd (II)
complexes were achieved by sonication and the conventional method. In addition to establish the structure by DFT studies and to explore
antimicrobial and anticancer activities of these novel compounds.
Methods: The precursor 2-substituted-5-amino-thiadiazoles (T1-T3), target ligands and their metal complexes were synthesized by ultra-
1
sonication and conventional means. The isolated products were thoroughly characterized by physical and spectroscopic techniques including H-
13
NMR, C-NMR and IR spectroscopy. All characterized compounds were screened for antimicrobial activities using well diffusion method, and MTT
assay was performed for cytotoxicity.
Results: All novel compounds were synthesized by a green route i.e. ultra sonication and a noticeable improvement in yield with shorter reaction
time than the conventional method were observed. The octahedral geometry was proposed for Ni (II)/Cu (II) complexes whereas square planar for
Pd (II) complexes on the basis of the spectral techniques which were supported by DFT analysis by Gaussian03. On the analysis of antimicrobial
activities, the compound T7 and T10 showed maximum antibacterial and antifungal activities respectively. However, compounds T25, T37, T31
found to be a potential cytotoxic compound with IC50 value 0.469, 0.865 and 1.131 μM respectively.
Conclusion: Analysis of synthetic protocol, it could be concluded that ultra-sonication is the better method to synthesize these potential biological
active moiety. On the whole Cu (II) and Ni (II) complexes showed promising activity towards all microorganisms while Pd (II) complex emerged an
excellent moiety in carcinoma cell line.
Keywords: Ultrasonication, Substituted-thiadiazoles, Ketones (5-bromo-isatin/chalcone/acridone), DFT calculations, Antimicrobial and anticancer studies
©
2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2017v9i4.17130
INTRODUCTION
compounds and used as a raw material for synthesis of various
drugs and heterocyclic compounds. Because of the excellent
chelating behaviour of Schiff bases, the importance of their metal
complexes are well documented in the literature [17]. Additionally,
the Density functional theory (DFT) was used by the various
researcher to optimize the structure of synthesized metal-ligand
complexes [18-20]. Keeping all these observations in mind, some 2-
substituted-5-amino-thiadiazoles (T1-T4) were synthesized by
sonochemical as well as conventional method. These characterized
products were further condensed with 5-bromoisatin/ chalcone/
acridone, with an aim to achieve the compounds (ligands, T5-T16)
having better antimicrobial activity and lesser cytotoxicity. As metal
complexes were found to be more active against various microbes and
pathogen, these isolated ligands (T5-T16) were further complexed
with Ni, Cu, Pd chlorides to get their metal complexes. All novel
compounds were characterized by spectral techniques. The paper
reports the synthesis and characterization studies of the novel
complexes for antimicrobial activities, anticancer and computational
studies using a B3LYP/3-21G basis set for geometrical optimization of
complexes.
The nitrogen, sulphur bearing heterocyclic systems constitutes the
core structure of a number of biologically interesting compounds in
living organisms, natural products, drugs and many more substances
useful to mankind. Their synthesis and evaluation have always drawn
the attention of chemists and biologists over the years. Among them, 1,
3
, 4-thiadiazoles is a promising structure in medicinal chemistry and
drug discovery [1] due to their diverse biological activities such as
antihypertensive, anti-inflammatory, anti-bacterial, anti-amoebic [2],
anti-HIV [3], antitumor and cytotoxic [4] activity. Moreover, they acts
as a building block for the synthesis of various biologically active
intermediates and derivatives [5, 6]. Additionally, Schiff bases derived
from amino-thiazoles have been shown to possess promising
applications in various biological modeling and activities [7].
With the ever-increasing problem of microbe resistance to current
antimicrobial drugs, there is an urgent need for new classes of
compounds that will efficiently inhibit the growth of pathogenic
microorganisms. So designing molecules bearing suitable functionalities
for the creation of well-defined structural design is one of the major
goals in chemistry. Additionally, increase in high throughputs biological
screening and accelerated development of new biological targets has
MATERIALS AND METHODS
increased the demand on synthetic chemists to produce
a new
Reagents such as thiosemicarbazide hydrochloride, acetic acid, p-
chlorobenzoic acid, p-nitrobenzoic acid and 5-bromoisatin were
purchased from Across Ltd and used as received. However, chalcone
compound for testing in less time in sync with environment-friendly
technique. In this context, the use of ultrasonic irradiation [8-12] to
activate organic reactions in the heterogeneous/homogeneous system
has recently taken on a new dimension. The prominent features of
ultrasound approach are to enhance reaction rates, the formation of
purer products in high yields, shorter reaction time and milder
conditions as compared with traditional methods.
[14] and acridone [16] were synthesized by following reported
methods. All the solvents were of analytical grade and were distilled
before used. Melting points are uncorrected. The solid IR (Infrared
spectroscopy). spectra were recorded in KBr on Perkin Elmer-
Spectrum-Lambda-25 spectrophotometer at GITAM University,
1
Structure-based pharmacophore approaches have become widely
used in drug discovery and design. A survey of the literature reveals
that isatin [13], chalcone [14, 15] and acridone [16] are versatile
Visakhapatnam; however, H-NMR (proton nuclear magnetic
13
resonance) and C-NMR (Carbon-13 Nuclear Magnetic Resonance)
spectra were obtained using Bruker 400 MHz NMR facility at IISc,

Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
Bangalore. Chemical shift values were reported in parts per million
ppm) using TMS as an internal standard and DMSO-d /CDCl as NMR
Synthesis of 2-substituted-5-amino-thiadiazoles
-substituted-5-amino-thiadiazoles was synthesised accordance to
the literature reported procedure [21] and by an alternative
greener method, ultra sonication in which pleasing similar
outcomes was found. The progress of the reaction was monitored
by TLC plates.
(
6
3
2
solvents. Ultra sonication (US) experiments were performed on a
probe sonicator (12/20 mm probe) with an ultrasonic processor (250
W) operating at a fixed frequency of 50 Hz with speed 238 rpm.
Quantum chemical calculations were carried with the Gaussian 03v
package using DFT/B3LYP/3-21G basis set to understand the
electronic structure and to correlate with the experimental findings.
The structural studies were drawn with Avogadro and the structures
were visualized with Gauss view for optimisation.
The final product was recrystallized from boiling water (Scheme 1).
The isolated product was characterized by spectral means and found
congruity structurally with the expected structure.
Scheme 1
Synthesis of substituted thiadiazole schiff’s bases (T5-T16) by
conventional/ultra-sonication method
ultrasonicated under probe sonicator (table 1). The completion of
the reaction was monitored by TLC. The solid mixture from both the
methods was filtered, dried, recrystallized. The synthesized
compounds were characterized by
analysis.
A mixture of substituted thiadiazole (T1-T4, 1 mmol) and ketones
1
H NMR, 13C NMR and mass
(
5-bromoisatin, chalcone, acridone, 1.0 mmol) was refluxed/
Scheme 2
Table 1: Comparison of reaction kinetics of conventional and ultrasonic irradiation methods for synthesis of compounds T5-T16
S. No.
Compound
Reaction time
US(min)
10
20
25
25
20
15
20
20
20
15
25
% Yield
US*
82
91
80
82
88
74
89
81
92
82
90
Conv.(h)
8
6
9
Conv.*
70
72
59
71
65
54
74
70
80
76
82
79
1
2
3
4
5
6
7
8
9
T-5
T-6
T-7
T-8
8
T-9
10
12
12
8
9
7
T-10
T-11
T-12
T-13
T-14
T-15
T-16
1
1
1
0
1
2
7
10
20
91
1
T5: [5-bromo-2-((5-methyl-1,3,4-thiadiazol-2-yl)imino)indolin-3-one]
1670(C=O),1627,1520(C=N); HNMR(δ ppm):6.7-6.9(Ar-H),3.3(NH),
-
1
13
(
C
11
H
7
BrN
4
OS)321.95: IR(cm ): 3390 (NH), 3105(Ar-H),2989(CH
3
),
2.3(CH
3
); CNMR(δppm):26.3(CH
3
),113.6,115.6,120.3,129.8, 145.1,
1
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Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
1
47.8(Ar-C),159,150(thiazole carbons);m/e: 323.95; Analysis: Calcd
T12:
[(E)-N-((E)-1,3-diphenylallylidene)-5-(4-nitrophenyl)-1,3,4-
-
1
C, 40.88; H, 2.18; N, 17.34 Found: C, 40.89; H, 2.20; N, 17.35.
thiadiazol-2-amine]
(C23H
16
N
4
O
2
S);412.10;IR(cm ):3610
(OH),
1
3
130(ArH),1602(N=CH),1514(C=N); HNMR(δppm):9.9(O-H);8.05
T6: [5-bromo-2-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)imino)
indolin-3-one] (C16
13
(
N=CH),6.7-7.3(Ar-H),6.1-6.0(HC=CH), CNMR(δ
ppm):
109.4-
-
1
H
9
BrN
4
O
2
S);401.24;IR(cm ):3610 (OH), 3316
1
1
3
11.6(HC=CH); 116,118,130(Ar-C),154,162,172 (Oxazole Carbons),
67.3(azomethine carbon); m/e: 412.08; Analysis: Calcd C, 66.97; H,
.91; N, 13.58; O, 7.76; Found: C, 67.19; H, 3.21; N, 14.22.
1
(
NH),3108(Ar-H),1672(C=O),1626,1514 (C=N); HNMR(δppm):7.4-
13
7
1
2
.8(Ar-H),3.4(NH), CNMR (δppm):126.1, 126.7,129.5,130(Ar-C),
60,168 (Oxazole carbons); m/e: 401.96;Analysis: Calcd C, 47.89; H,
.26; N, 13.96; Found: C, 47.92; H, 2.18; N, 13.98.
T13:
amine](C16
[N-(9,10-dihydroacridin-9-yl)-5-methyl-1,3,4-thiadiazol-2-
-
1
H
14
N
4
S);292.08;IR
(cm ):3325(NH),3130(Ar-H),2985
T7:
[5-bromo-2-((5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)imino)
1
(
CH
H),3.8(NH), CNMR(δ ppm): 116,118,130,134,(Ar-C), 162,170
Oxazole carbons); m/e: 294.08; Analysis: Calcd C, 65.28; H, 4.79; N,
9.03;Found: C, 65.20; H, 4.89; N, 19.09.
3
),1626,1514(C=N); HNMR(δppm):6.7-7.3(Ar-
-1
indolin-3-one] (C16
H BrClN
8
4
OS);419.68;IR(cm ):3226 (NH),3130
13
1
(
8
ArH),1669(C=O),1602(N=CH), 1514(C=N); HNMR(δppm): 9.9(O-H);
(
1
.05(N=CH),6.7-7.3(Ar-H),3.5(NH),13CNMR(δppm):116,118,130 (Ar-
C),154,162,172(Oxazole Carbons),167.3(azomethine carbon); m/e:
4
1
19.93; Analysis: Calcd C, 45.79; H, 1.92; N, 13.35;Found: C, 45.80; H,
.90; N, 13.33.
T14: [4-(5-((9,10-dihydroacridin-9-yl)amino)-1,3,4-thiadiazol-2-yl)
-
1
phenol]
(C21
H
16
N OS);370.09;IR(cm ):3690(-OH),3128(Ar-H),610
4
1
(
N=CH),1549-1536(C=N),1335-1064(C-O); HNMR
.15(OH),7.6-7.9(Ar-H),6.79-6.77(Ar-H),3.3(-NH), CNMR(δ
(δ
ppm):
T8:
[5-bromo-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)imino)
13
9
-
1
indolin-3-one] (C16
H
8
BrN
5
O S);430.24;IR(cm ):3301(NH),3120(Ar-
3
ppm):111.5,125,132(Ar-C),153.67,158 (thiazole carbons), 164.31
azomethine carbon); m/e: 372.10; Analysis: Calcd C, 67.72; H, 4.33;
1
H),1671(C=O),1605(N=CH),1545(C=N); HNMR:
(δppm):
8.05
CNMR (δppm):
11.53, 125,132(Ar-C), 150, 154.68(thiazole carbons),163.3
(
13
(
1
N=CH),7.5-7.8(Ar-H),6.7-6.8(Ar-H), 3.2(NH),
N, 15.04; Found: C, 67.79; H, 4.67; N, 15.11.
(
1
azomethine carbon); m/e: 430.24; Analysis: C, 44.67; H, 1.87; N,
6.28; Found: C, 44.69; H, 1.86; N, 16.29.
T15: [5-(4-chlorophenyl)-N-(9,10-dihydroacridin-9-yl)-1,3,4-thiadiazol-
(cm-1):
2-amine](C21
H
13ClN
4
S)
388.05:
IR
3120(Ar-
1
H),1615(N=CH),1514(C=N); HNMR(δ ppm):7.4-7.8(Ar-H),6.7-6.8(Ar-
H),3.31(-NH), CNMR(δ
T9:
amine] (C18
1
6
1
3
[N-((E)-1,3-diphenylallylidene)-5-methyl-1,3,4-thiadiazol-2-
13
ppm):126,126.7,129.5,130(Ar-C)160,169
-
1
H
15
N
3
S);305.10: IR (cm ): 3130(Ar-H), 2987(-CH
3
),
(
Oxazole Carbons), 165.3(azomethine carbon); m/e: 390.07; Analysis:
1
626(HC=CH),1514(C=N), 1465; HNMR(δ ppm):7.5-7.9 (Ar-H),6.1-
Calcd C, 64.53; H, 3.87; N, 14.33; Found: C, 64.41; H, 3.82; N, 14.20.
13
.0(HC=CH),2.3(CH
3
); CNMR(δppm):110.1-111.9(HC=CH);
119,
26.5,128.7,130.3 (Ar-C), 152(C=C),162,169 (Oxazole carbons);m/e:
05.40; Analysis: Calcd C, 70.79; H, 4.95; N, 13.76; Found: C, 69.19;
T16: [N-(9,10-dihydroacridin-9-yl)-5-(4-nitrophenyl)-1,3,4-thiadiazol-
-
1
2-amine](C21
H
15
N
5
O
2
S);399.08;IR (cm ): 3140(Ar-H), 1610(N=CH),
ppm): 8.2(N=CH),7.2-7.6(Ar-H),3.35(-NH),
1
H, 4.86; N, 12.47.
1514(C=N); HNMR(δ
13
CNMR(δ ppm):128.4,129.4,133.8,134.6(Ar-C);161,170, (Oxazole
Carbons),168(azomethine carbon); m/e: 401.09;Analysis: Calcd C,
2.83; H, 3.77; N, 17.45; Found: C, 62.91; H, 3.68; N, 17.55.
T10: [4-(5-((E)-((E)-1,3-diphenylallylidene)amino)-1,3,4-thiadiazol-
2
H),1536(C=N); HNMR (δ ppm):9.66(OH),8.1(N=CH),7.6-7.9(Ar-H),
6
-
1
-yl)phenol] (C23
H
17
N OS); 383.11;IR(cm ):3469(-OH),3128(Ar-
3
6
1
13
.1-5.9(HC=CH); CNMR(δppm):109.1-110.9(HC=CH);
111.4,125,
General procedure for the preparation of metal complexes
1
32(Ar-C),154.6, 159(thiazole carbons),165.3(azomethine carbon);
The Ni, Cu and Pd complexes of the above novel ligands (T5-T16)
were prepared by the literature reported conventional method
m/e: 383.09; Analysis: Calcd C, 72.04; H, 4.47; N, 10.96;Found: C,
2.92; H, 4.95; N, 11.22.
7
[
22]. Further, the promising utility of ultrasonic radiation was
T11:
[(E)-5-(4-chlorophenyl)-N-((E)-1,3-diphenylallylidene)-1,3,4-
also explored and found that 25 min of ultrasonication were
sufficient to get similar results.
-1
thiadiazol-2-amine] (C23
H
16ClN S);401.08;IR (cm ): 3658(-OH), 3140
3
1
(Ar-H),1610(N=CH),1514(C=N); HNMR(δ ppm):8.2(N=CH),7.2-7.6(Ar-
13
The complexes isolated from both the methods were compared
by identical TLC spots and melting point. The isolated complexes
were characterized by various spectral methods and gave
satisfactory results for expected structure fig. 1.
H),6.1-6.0(HC=CH), CNMR(δppm):109.5-110.8(HC=CH); 128.4, 129.4,
33.8,134.6(Ar-C);161,170(Oxazole Carbons),168(azomethine
1
carbon); m/e: 401.05; Analysis: Calcd C, 68.73; H, 4.01; N, 10.46;
Found: C, 67.51; H, 4.68; N, 10.21.
Fig. 1: Structure of metal complexes
-
1
-1
T
3
5
-Ni/[NiT
610 (OH),3114(Ar-H), 2988(CH
Analysis: Calcd C,27.03; H,2.27; N, 11.46; Ni, 12.01; Found: C, C, 27.00; H,
.25; N, 11.47;Ni,12.25.
5
Cl
2
.(H
2
O)
2
]
(T17)
C
3
11
H
11BrCl
2
N
4
NiO
3
S; 488.80;IR(cm ):
T
5
-Pd/[PdT
5
Cl
2
]
(T19) (C11
7
H BrCl
2
N
4
OPdS); 500.49;IR(cm ):
),1666(C=O),1545(C=C),1543 (C=N);
3115(Ar-H), 2988(CH
3
), 1665 (C=O),1544 (C=C),1542(C=N);
Analysis: C, 26.40; H, 1.41; N, 11.19;Pd, 21.26; Found: C, 26.39; H,
1.40; N, 11.17;Pd, 21.24
2
S; 493.65;IR(cm-
T -Ni/[NiT
6
Cl
.(H
O)
] (T20) C16
H
13BrCl
NiN
O
S; 566.87;IR(cm ):
-1
T
)
5-Cu/[CuT
:3609(OH),3113(Ar-H), 2987(CH
5
Cl
2
.(H
2
O)
2
]
(T18)
C
3
11
H
11BrCl
2
N
4
CuO
3
6
2
2
2
2
4
4
1
),1664(C=O),1542(C=C),1542(C=N);
3105(Ar-H),3611(OH), 1632(C=O),1510(C=N); Analysis: Calcd C,
33.90; H, 2.31; N, 9.88; Ni, 10.35; Found: C, 33.89; H, 2.30; N, 9.87; Ni,
10.34
Analysis: Calcd C, 26.76; H, 2.25; N, 11.35; Cu, 12.87;Found: C, 26.74; H,
.26; N, 11.34; Cu, 12.85.
2
1
87

Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
T
)
3
6-Cu/[CuT
6
Cl
:3103(Ar-H),3609(OH),1630(C=O),1512(C=N); Analysis: Calcd C,
3.61; H, 2.29; N, 9.80; Cu, 11.11; Found: C, 33.60; H, 2.28; N, 9.78;
Cu, 11.09
2
.(H
2
O)
2
] (T21) C16
H
13BrCl
2
CuN
4
O
4
S; 571.72;IR(cm-
T
11-Pd/[PdT12Cl
2
]
(T37)
):3137(Ar-H),1606(N=CH),1514 (C=N);Analysis: Calcd C, 47.69; H,
2.78; N, 7.25; Pd, 18.37; Found: C, 47.68; H, 2.77; N, 7.23; Pd, 18.36
C
23
H
16Cl
3
N
3
PdS;
579.24;IR(cm-
1
1
T
12-Ni/[NiT12Cl
2
.(H
O)
2 2
]
(T38)
C
23
H20Cl
2
N
4
NiO
S; 578.09;IR(cm-
4
-
1
1
T
6
-Pd/[PdT
6
Cl
2
]
(T22)
C
16
H
9
BrCl
2
N
4
O
2
PdS; 578.56;IR(cm ):
):3608(OH),3128(Ar-H), 1605(N=CH),1514(C=N); Analysis: Calcd C,
47.79; H, 3.49; N, 9.69; Ni, 10.15; Found: C,, 47.78; H, 3.46; N, 9.66;
Ni, 10.14
3101(Ar-H), 3612(OH), 1630 (C=O),1512(C=N); Analysis: Calcd C,
33.22; H, 1.57; N, 9.68; Pd, 18.39; Found: C, 33.20; H, 1.55; N, 9.67;
Pd, 18.48
T
12-Cu/[CuT12Cl
2
.(H
2
O)
2
] (T39) C23
H
20Cl
2
N
4
CuO
S; 582.95; IR (cm-
4
S; 585.31; IR(cm-
1
): 3618(OH),3126(Ar-H), 1604(N=CH),1512(C=N); Analysis: Calcd
C, 47.39; H, 3.46; N, 9.61;Cu, 10.90; Found: C,, 47.37; H, 3.44; N,
9.60;Cu, 10.88
T
)
7
-Ni/[NiT
7
Cl
2
.(H
2
O)
2
] (T23) C16
H
12BrCl
3
N
4
NiO
3
1
:3607(OH),3129(Ar-H), 1607(N=CH),1517(C=N);Analysis: Calcd C,
3
1
2.83; H, 2.07; N, 9.57; Ni, 10.03; Found: C, 32.82; H, 2.06; N, 9.55; Ni,
0.00
T
12-Pd/[PdT12Cl
2
]
(T40)
23
C H
16Cl
2
N
4
O
PdS; 589.79;IR(cm-
2
1
T
)
3
7-Cu/[CuT
7
Cl
:3608(OH),3133(Ar-H),1610(N=CH),1515(C=N);Analysis: Calcd C,
2.56; H, 2.05; N, 9.49; Cu, 10.77; Found: C, 32.54; H, 2.04; N, 9.47;
Cu, 10.96
2
.(H
2
O)
2
] (T24) C16
H
12BrCl
3
N
4
CuO
3
S; 590.17; IR(cm-
):3128(Ar-H),1607(N=CH),1516 (C=N); Analysis: Calcd C, 46.84; H,
1
2.73;N, 9.50; Pd, 18.04; Found: C, 46.83; H, 2.72;N, 9.48; Pd, 18.00
T
13-Ni/[NiT13Cl
2
.(H
2
O)
2
]
(T41)
C
16
H
16Cl
2
N
4
NiO
),1628,1516(C=N);
2
S; 457.99;IR(cm-
1
)
:3678(-OH),3322(NH
2
), 3133(Ar-H), 2989(CH
3
T
)
3
7
-Pd/[PdT
7
Cl
:3609(OH),3130(Ar-H),1611(N=CH),1519(C=N):Analysis: Calcd C,
2.19; H, 1.35;N, 9.38; Pd, 17.83; Found: C, 32.17; H, 1.34; N, 9.36;
Pd, 17.82
2
]
(T25)
C
16
H
8
BrCl
3
N
4
PdO
3
S; 593.01;IR(cm-
Analysis: Calcd C, 41.96; H, 3.52; N, 12.23; Ni, 12.82; Found: C, 41.94;
H, 3.50; N, 12.20; Ni, 12.80
1
T
13-Cu/[CuT13Cl
:3679(-OH),3326(NH
2
.(H
2
O)
2
] (T42) C16
H
16Cl
2
N
3
CuO
),1628,1515 (C=N);
2
S; 462.84;IR(cm-
1
)
2
), 3134(Ar-H), 2990(CH
3
T
)
8
-Ni/[NiT
8
Cl
2
.(H
2
O)
2
] (T26) C16
H
12BrCl
2
N
5
NiO
S; 595.87;IR(cm-
5
Analysis: Calcd C, 41.52; H, 3.48; N, 12.10;Cu, 13.73; Found: C, 41.50;
H, 3.47; N, 12.08;Cu, 13.72
1
:3613(OH),3118(Ar-H), 1603(N=CH),1540(C=N);Analysis: Calcd C,
3
3
2.25; H, 2.03; Br, 13.41; Cl, 11.90; N, 11.75; Ni, 9.85; Found: C,
2.24; H, 2.00; Br, 13.40; Cl, 11.87; N, 11.72; Ni, 9.82
-
1
T
13-Pd/[PdT13Cl
2
2
]
(T43)
C
16
H
16
N
4
O
2
PdS; 434.81;IR(cm ):3327
(
NH ),3132(Ar-H),2989 (CH
3
),1629,1518(C=N);Analysis: Calcd C,
T
)
8-Cu/[CuT
8
Cl
2
.(H
2
O)
2
] (T27) C16
H
12BrCl
2
N
5
CuO
5
S; 600.72;IR(cm-
44.20; H, 3.71; N, 12.89; Pd, 24.48; Found: C, 44.19; H, 3.69; N, 12.88;
Pd, 24.45
1
:3612(OH),3116(Ar-H),1607(N= CH),1543(C=N); Analysis: Calcd C,
3
1.99; H, 2.01; N, 11.66; Cu, 10.58; Found: C, C, 31.97; H, 2.00; N,
T
)
14-Ni/[NiT14Cl
2
.(H
2
O)
2
]
(T44)
C
21
H
18Cl
2
N
4
NiO
3
S; 536.06;IR(cm-
11.64; Cu, 10.57
1
:3686(-OH),3126(Ar-H), 612(N=CH),1545-1535(C=N),1332-1060
PdS; 607.56; IR(cm-
(C-O) Analysis: Calcd C, 47.05; H, 3.38;N, 10.45; Ni, 10.95; Found: C,
47.03; H, 3.37;N, 10.44; Ni, 10.94
T
8
-Pd/[PdT
8
Cl
2
]
(T28)
C
16
H
8
BrCl
2
N
5
O
3
1
)
:3118(Ar-H),1609(N=CH), 1547(C=N);Analysis: Calcd C, 31.63; H,
1
.33;N, 11.53;Pd, 17.52; Found: C, 31.62; H, 1.32;N, 11.50;Pd, 17.51
S; 540.91;IR(cm-
):3688(-OH),3124(Ar-H),613(N=CH),1546-1535(C=N),1335-1060
(C-O) Analysis: Calcd C, 46.63; H, 3.35; N, 10.36; Cu, 11.75; Found: C,
T
14-Cu/[CuT14Cl
2
.(H
2
O)
2
] (T45) C21
H
18Cl
2
N
4
CuO
3
1
S; 471.03;IR (cm-
NiO
T
9
-Ni/[NiT
9
Cl
:3615(OH),3128(Ar-H),
989(CH ),1622(HC=CH),1510(C=N),1463; Analysis: Calcd C, 45.90;
H, 4.07; N, 8.92; Ni, 12.46; Found: C, 45.89; H, 4.05; N, 8.90; Ni, 12.44
2
2 2
.(H O) ]
(T29)
18
C H19Cl
2
N
3
2
1
)
46.62; H, 3.33; N, 10.34; Cu, 11.72
2
3
-1
T
14-Pd/[PdT14Cl ] (T46) C23
2
H N
18 4
O PdS; 512.88;IR(cm ):3686(-
3
OH),3122(Ar-H),610(N= CH),1545-1533(C=N),1333-1062(C-O):
Analysis: Calcd C, 49.18; H, 3.54; N, 10.92; Pd, 20.75; Found: C, 49.16;
H, 3.55; N, 10.90; Pd, 20.73
T
)
9-Cu/[CuT
:3614(OH),3127(Ar-H), 2985(CH
9
Cl
2
.(H
2
O)
2
] (T30) C18
H
3
19Cl
2
N
3
CuO
2
S; 475.88;IR (cm-
1
), 1624(HC=CH),1512(C=N),
1
4
464; Analysis: Calcd C, 45.43; H, 4.02; N, 8.83; Cu, 13.35; Found: C,
5.41; H, 4.00; N, 8.82; Cu, 13.33
T
)
15-Ni/[NiT15Cl
2
.(H
2
O)
2
] (T47) C21
H
17Cl
3
N
4
NiO
2
S; 554.50; IR (cm-
1
:3675(-OH),3118(Ar-H), 1612(N=CH),1510(C=N); Analysis: Calcd
-
1
T
9
-Pd/[PdT
9
Cl
),1622 (HC=CH),1510(C=N), 1466;Analysis: Calcd C,
4.79; H, 3.13; N, 8.70; Pd, 22.05; Found: C, 44.76; H, 3.12; N, 8.69;
Pd, 22.02
2
] (T31) C18
H15Cl
2
N PdS; 480.72;IR(cm ):3129(Ar-
3
C, 45.49; H, 3.09; N, 10.10; Ni, 10.58; Found: C, 45.48; H, 3.05; N,
10.08; Ni, 10.57
H),2986(CH
4
3
-1
T
15-Cu/[CuT15Cl
2
.(H
2
O)
2
] (T48) C21
H
17Cl
3
N
4
CuO S; 559.36;IR (cm ):
2
3
677(-OH),3115(Ar-H),1609(N=CH),1508(C=N); Analysis: Calcd C,
T
)
5
1
10-Ni/[NiT11Cl
2
.(H
:3610(OH), 3466(-OH), 3125(Ar-H),1534(C=N); Analysis: Calcd C,
0.31; H, 3.85; N, 7.65; Ni, 10.69; Found: C, 50.30; H, 3.83; N, 7.64; Ni,
0.67
2
O)
2
]
(T32)
C
23
H
21Cl
2
N
3
CuO
3
S; 549.10; IR(cm-
45.09; H, 3.06; N, 10.02; Cu, 11.36; Found: C, 45.08; H, 3.05; N, 10.00;
Cu, 11.33
1
T
)
15-Pd/[PdT15Cl
2
]
(T49)
C
21
H
13Cl
3
N
PdS; 566.20;IR (cm-
4
1
:3117(Ar-H),1607(N=CH), 1506 (C=N); Analysis: Calcd C, 44.55; H,
T
)
4
10-Cu/[CuT11Cl
2
.(H
:3610(OH),3467(-OH), 3124(Ar-H),1532(C=N);Analysis: Calcd C,
9.87; H, 3.82; N, 7.59; Cu, 11.47; Found: C, 49.86; H, 3.80; N, 7.58;
Cu, 11.45.
2
O)
2
] (T33) C23
H
21Cl
2
N
3
CuO
3
S; 553.95;IR(cm-
2.31;N, 9.90; Pd, 18.80; Found: C, 44.54; H, 2.29;N, 9.88; Pd, 18.79
1
T
)
16-Ni/[NiT16Cl
2
.(H
2
O)
2
]
(T50)
C
21
H
17Cl
2
N
5
NiO
4
S; 565.06;IR(cm-
1
:3655(-OH),3137(Ar-H), 1609(N=CH),1512(C=N); Analysis: Calcd
C, 44.64; H, 3.03;N, 12.39; Ni, 10.39; Found: C, 44.63; H, 3.00;N,
12.37; Ni, 10.37
T
10-Pd/[PdT11Cl
2
]
(T34)
23
C H
17Cl
2
N
3
PdOS;
560.79;IR(cm-
1
)
:3608(OH),3465(-OH),3123(Ar-H),1534(C=N); Analysis: Calcd C,
T
)
16-Cu/[CuT16Cl
2
.(H
2
O)
2
] (T51) C21
H
17Cl
2
N
5
CuO
4
S; 569.91;IR (cm-
4
7
9.26; H, 3.06; N, 7.49;Pd, 18.98; Found: C, C, 49.24; H, 3.03; N,
.48;Pd, 18.97
1
:3653(-OH),3136(Ar-H),1612(N=CH),1509(C=N); Analysis: Calcd
C, 44.26; H, 3.01; N, 12.29; Cu, 11.15; Found: C, 44.24; H, 3.00; N,
12.28; Cu, 11.12
T
11-Ni/[NiT12Cl
2
.(H
2
O)
2
]
(T35)
C
23
H
20Cl
3
N
3
NiO
2
S; 567.54;IR(cm-
1
)
:3658(-OH),3138(Ar-H), 1608(N=CH),1515(C=N); Analysis: Calcd
T
)
2
16-Pd/[PdT16Cl
2
]
(T52)
:3138(Ar-H),1614(N=CH), 1510(C=N);Analysis: Calcd C, 43.73; H,
.27;Pd, 18.45; Found: C, 43.71; H, 2.25;Pd, 18.42
C
21
H
13Cl
2
N
5
PdO
S; 576.75;IR(cm-
2
C, 48.67; H, 3.55; N, 7.40; Ni, 10.34; Found: C, 48.66; H, 3.54; N, 7.39;
Ni, 10.78
1
T
)
11Cu/[CuT12Cl
2
.(H
2
O)
2
] (T36) C23
H
20Cl
3
N
3
CuO
2
S; 572.39;IR(cm-
Antimicrobial assay
1
:3656(-OH),3136(Ar-H), 1605(N=CH),1512(C=N); Analysis: Calcd
The synthesized compounds (T5–T52) were assessed for
antimicrobial assay (Ansari, et al., 2005) against gram negative
C, 48.26; H, 3.52;Cu, 11.10; N, 7.34; Found: C, 48.25; H, 3.51;Cu,
1.08; N, 7.33
1
1
88

Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
bacteria EC-Escherichia coli (MTCC 1687), PA-Pseudomonas
aeruginosa (MTCC 1688) and gram positive bacteria BS-Bacillus
subtilis (MTCC 441),SA-Staphylococcus aureus (MTCC 96), along
with a fungus CA-Candida albicans (MTCC 227) using the well
diffusion method. The compounds were dissolved in DMSO and
activity was determined using serial dilution method. The whole
procedure was carried out as reported [23]. Ciprofloxacin and
ketaconazole were used as antibacterial and antifungal reference
drugs,respectively. The zone of inhibition (mm) was determined
at 10 μg/ml concentration for each compound in triplicate
experiments; the values were averaged and are presented in
table 2.
Table 2: Antimicrobial activity of synthesized compounds (zone of inhibition* in mm at concentration 10 µg/ml)
Compounds
Bacteria
EC
19
24
24
17
15
12
22
21
-
16
14
16
25
15
28
15
16
16
28
20
18
20
35
-
Fungus
CA
16
12
14
-
17
24
23
10
11
20
19
8
15
11
18
21
-
21
15
12
11
19
-
PA
25
16
27
24
18
22
20
21
14
19
17
-
20
15
25
15
-
18
23
17
16
16
30
-
BS
13
22
19
20
17
15
18
14
18
16
-
17
19
16
21
18
-
SA
15
20
25
15
23
17
19
14
18
-
17
13
14
13
20
16
-
T5
T6
T7
T8
T9
T10
T11
T12
T13
T14
T15
T16
T21
T22
T23
T24
T26
T29
T33
T38
T44
T47
Cephaloflaxin
Ketoconazole
18
19
18
17
22
28
-
16
16
13
12
17
35
-
28
*
Results are the mean of triplicate experiments, (-) no inhibition was observed, EC-Escherichia coli, PA-Pseudomonas aeruginosa, BS-Bacillus subtilis,
SA-Staphylococcus aureus, CA-Candida albicans
Molecular DFT calculations
Table 3: IC50 of tested compounds for antitumor screening
against MDA-MB231 cancer cells
Quantum chemical calculations were carried with the Gaussian 03v
package using DFT with geometry optimization in the gaseous state
of complexes was carried out at the B3LYP level of theory 3-21G (d)
basis set [20]. The structural studies were drawn with Avogadro and
visualized with Gauss view for optimization. The analysis of frontier
molecular orbitals was also performed at the same level of theory.
The optimized geometrical parameters (bond lengths, bond angles
and dihedral angles), dipole movement, electrophilicity index,
wavelength and energy difference of the ground state for the ligand
Compounds
T6
T8
T11
T14
T15
T25
T31
IC50(µM)*
1.58
1.948
2.325
2.286
2.965
0.469
1.131
0.865
1.272
1.20
(
T9) and its Cu (II) complexes were estimated and similar results
T37
T46
were obtained for Ni (II) and Pd (II) complexes.
Standard (Cisplatin)
Cytotoxicity assay
*
IC50: values indicate the effective concentration of a compound
The cytotoxicity of the Schiff base and its metal complexes were
evaluated by MTT assay [22] against breast adenocarcinoma cells
required to achieve 50 % growth inhibition in µg/ml.
(
×
MDA-MB231). The cells were pre-incubated at a concentration of 1
10 cells/well and incubated with L-15 medium containing
4
RESULTS AND DISCUSSION
different concentrations (10, 1, 0.1, 0.01 and 0.001 µM) of
compounds for 24 and 48 h at 37 °C. The cell proliferation is based
on the ability of the mitochondrial succinate-terazolium reductase
system to convert 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide (MTT) to a blue coloured formazan [25]. The
test denotes the survival cells after toxic exposure. Then, 20 μl
Several modified methods for synthesis of novel biologically active
molecules including environmental-friendly methods were mentioned in
the literature. Among them, the use of ultrasonic waves in organic
synthesis came in light recently [26]. In the sonochemistry, due to
cavitation very high local temperatures and pressures generated and
consequently, products formed. As compared with traditional methods,
this technique is more convenient, easily controllable and high
producibility. Considering these facts and our interest to develop a new
synthetic route, synthesis of substituted thiadiazoles (T1-T4) and their
Schiff bases (T5-T16) with various ketones (5-bromoisatin, chalcone,
acridone) by ultrasonication/conventional method were accomplished
as depicted in Scheme 2 and 3 respectively.
MTT mixture was added and incubated for next
3 h. Each
experiment was done in triplicates and Cisplatin was used as a
standard drug. The formazen crystals were dissolved in DMSO and
spectrophotometric absorbance was measured using an ELISA
microplate reader at 570 nm. Finally, the efficacy of the test
compounds was evaluated by determining IC50 values by using
Graph Pad Prism software (table 3).
1
89

Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
Table 4: Moment of inertia of the studied compounds
Name of the compound
Moment of inertia
−45
2
1
×10 Kgm
I
x
I
y
I
z
T1
TC
T9
T30
0.53
4.86
15.8
53.2
4.83
42.4
59.6
76.3
5.26
47.1
64.3
106.3
The structures of the all synthesized compounds were established
on the basis of their FTIR and NMR data. Identical TLC and melting
points were observed for the product obtained from both the
methods. The IR of substituted thiadiazole (1-4) showed
and wavelength. The experimental wavenumbers for these
complexes (T1, TC, T9 and T30) are comparable with the
computed wave numbers (fig. 2). These wavenumbers exhibit
bathochromic and hypsochromic shifts of complexes in functional
group regions as shown in fig. 3(a, b). The optimize structure of
ligand and its Cu complex corresponding to frontier contours was
given in fig. 3(c). There is an increase in dipole moment and
moment of inertia (table 4) from T1 to T30 and energy gap is
reduced indicating the ability of ease of bonding activity and
structure indicates the high donor activity.
-
1
characteristic peaks at 3312 and 3245 cm , attributed to a primary
amine group. Apart from major functional groups observed in the IR
spectra of the compounds 5-16 showed a stretching band at 1620-
-
1
1
605 cm
disappearances of NH
-12; 13-16 were further supportive of condensation of the amino
corresponding to azomethine [27] group. The
2
and CO (carbonyl) peaks in the IR spectra of
9
group of substituted thiadiazole with the carbonyl group of ketone.
This was further confirmed by their 1HNMR spectra. The
azomethine proton peak was clearly observed [28] in the Schiff
bases (5-16) at δ 8.5-7.9 ppm. Other protons peaks were found to be
well consistent with the expected structures.
Although the IR spectra were recorded in the solid state and DFT-
calculated frequencies in gas phase, the proposed relatively
simplified model provides a good agreement for the functional
group and metal–ligand bonding frequencies in novel compounds.
However, the significant variations were observed for the metal
complexes indicating the octahedral geometry of the metal
complexes due to the involvement of chelation. The responsible
spectral properties i.e. dipole movement, electrophilicity index
wavelength and energy difference for the formation of the
structure due to electron transfer depicted in fig. 4.
To establish the expected structure of synthesized ligands and
their metal complexes, DFT study of the novel synthesized
complexes (T1, TC, T9 and T30) were performed to study for (i)
comparison of wave numbers (ii) optimized structural geometry
(
iii) frontier orbital with energy differences (iv) Dipole moment
Fig. 2: Experimental and computed wave numbers of the T1, T9, T30 compound
Fig. 3: Frontier contour of studied ligand T9 and its Cu complex (T30) with optimized its structures
1
90

Anjali et al.
Int J Pharm Pharm Sci, Vol 9, Issue 4, 185-192
(a)
(b)
(c)
(d)
Fig. 4: Computed energy difference, wavelength, dipole moment and electrophilicity index profile of studied complex
Antimicrobial evaluation results of all novel compounds against bacteria
and fungi are encouraging. The analysis of Schiff bases and their
complexes (T5-T52) revealed that the isatin containing ligands showed
significant activity against all bacterial strain. However, chalcone ligands
shows better activity than acridone ligands in the case of gram-positive
bacteria (BS and SA), while in the case of fungus the followed trend was
chalcone> acidone> isatin. Among the in vitro antibacterial and
antifungal studies Cu (II) and Ni (II) complexes showed better activities
then their parent ligands thus advocating that the metal-ligand
complexes shows a significant role in developing the lead drug molecule.
Designing more polar compounds may overcome solubility problems of
synthesized compounds, and might achieve more active compounds.
However, Pd (II) complexes were emerged better candidate for
antitumor agents [23] with IC50 values of 0.469 and 0.865 µM.
complexes exhibited higher antimicrobial activity than respective
free ligands. Furthermore, the chalcone and isatin containing
compounds were found more active than acridone. However, its
metal complexes displayed better activity in all the cases. Ni and Cu
complexes exhibited better antimicrobial activities, however, Pd
complexes as better cytotoxic compounds. We hope that our findings
will be helpful in the design and synthesis of more effective but safe
anticancer/antimicrobial drugs.
ACKNOWLEDGEMENT
The authors are thankful to the GITAM University for providing
necessary facility to do this work and University Grants Commission
(
4
UGC, Government of India) for providing financial assistance [F. No.
2-239/2013 (SR)].
CONCLUSION
AUTHOR CONTRIBUTION
The present work reports greener approach ultrasonication (US) for
the synthesis of thiadiazole analogs along with their metal
complexes. It was observed that ultrasonication based method
provides a better yield in relatively less amount of time. Moreover,
this method (US) is more energy efficient, operationally simple and
environmentally benign and hence is a worthwhile addition to the
existing methods. All the synthesized compounds were
characterized well by routine spectral methods. DFT analysis of few
ligands and their metal complexes were also done to establish their
expected structure and found consistent to experimental values. On
the basis of spectral and DFT analysis, octahedral geometry was
ascertained for metal complexes. All compounds were also evaluated
for in vitro antimicrobial activities and few potential metal
complexes with ligands in vitro anticancer activities. In general,
A. J. conceived the study and designed the experiments. P. B.
performed the experimental synthesis. Computational experiments
along and analysis were carried out by SD and CH. R. K. All the
authors made contributions to the writing of the manuscript and
approved the final version.
CONFLICT OF INTERESTS
Declared none
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