Synthesis and antimicrobial study of some transition metal complexes
of novel bidentate heterocyclic ligand: 3-(((8-hydroxyquinolin-5-yl)
amino) methyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-thione (HAMPOTe)
M.F.Tank*1, G.D.Acharya2
1Lecturer
In Chemistry, Government Polytechnic, Palanpur-385001(Gujarat), India.
2Head,
Dept. of Chemistry, R.R.Mehta College of Science &
C.L.Parikh College of Commerce, Palanpur-385001(Gujarat), India.
E-mail: drgdacharya@gmail.com
Abstract
A novel series of transition metal complexes have been synthesized from the
reaction
of
3-(((8-hydroxyquinolin-5-yl)amino)methyl)-5-phenyl-1,3,4-oxadiazole-
2(3H)-thione (HAMPOTe) with transition metal salts. The structures of these
compounds have been elucidated by elemental and spectral analysis. Furthermore,
compounds were screened for in vitro antimicrobial activity against the representative
panel of two Gram-positive and two Gram-negative bacteria and two strains of fungus.
The various compounds show potent inhibitory action against test organisms.
Keywords:
5-phenyl-1,3,4-oxadiazole-2(3H)-thione;
5-amino-8-hydroxyquinoline
(5AHQ); Spectroscopic studies; Antimicrobial activity.
1.
Introduction
In recent decades, the construction of metal–organic coordination architectures
has witnessed tremendous growth because of their intriguing structures and potential
properties [1-4]. A large number of oxadiazole derivatives have been prepared and many
of these compounds have shown a wide spectrum of antimicrobial activity [5-7].The
observation that some oxadiazoles with different substituents at different location on the
heterocyclic ring resulted in fungicidal [8] and antibacterial agents [9] of various
potencies. Since their discovery during the 20th century, antimicrobial agents
(antibiotics and related antimicrobial drugs) have substantially reduced the threat posed
by infectious diseases. The use of these "wonder drugs", combined with improvements
in sanitation, housing,
and nutrition, and the advent of widespread immunization
programmes [10], and the development of numbers of antimicrobial agents for treatment
1
of microbial infections [11-13] has led to a dramatic drop in deaths from diseases that
were previously widespread, untreatable, and frequently fatal. These gains are now
seriously jeopardized by another recent development: the emergence and spread of
microbes that are resistant to cheap and effective firstchoice, or "first-line" drugs.
Worldwide emergence of multi-resistant microbial strains is a growing concern which
requires a multi-pronged research strategy [14,17]. Hydroxyquinoline is a privileged
structural moiety observed in many biologically active natural products, and is used as
the source for many drugs diversely prescribed among a wide range of pathologies
including neurodegenerative diseases [18], parasitic amoebic dysentery disease [19],
and herpes viral diseases [20]. More specifically, 8-hydroxyquinoline moiety has been
mostly used for its capacity to strongly chelate metal ions, particularly Cu2+ and Zn2+
[21]. 5-amino-8-hydroxyquinoline (5AHQ) can be synthesized facilely and studied
extensively [22]. Chelating ligands containing O and N donor atoms show broad
biological activity and are of special interest because of the variety of ways in which
they are bonded to metal ions [23]. The presence of transition metals in human blood
plasma indicates their importance in the mechanism for accumulated storage and
transport of transition metals in living organisms [24]. Transition metals play a key role
in biological systems such as cell division, respiration, nitrogen fixation and
photosynthesis [24]. Hence it was thought of interest to accommodate oxadiazole and
5AHQ moieties in a single molecular framework and to synthesize some new ligand and
metal complexes for enhancing biological activity.
The present paper deals with the synthesis and characterization of a novel metal
complexes with Fe2+, Co2+, Ni2+, Mn2+, Cu2+and Zn2+ metal ions and their antimicrobial
activity.
2.
Experimental
The contents of carbon, hydrogen and nitrogen were analyzed with a Perkins
Elmer (USA) 2400-II CHN analyzer. The metal contents of the metal complexes were
analyzed by EDTA titration. The melting points were checked using a standard open
capillary method and are uncorrected. Infrared spectra (4000 - 400 cm-1) were
recorded on a Nicolet-400D spectrophotometer using KBr pellets. 1H NMR spectra were
recorded on a model Advance 400 Bruker FT-NMR instrument and DMSO-d6 was used
2
as a solvent. The magnetic moments were obtained by Gouy’s method using mercury
tetrathiocyanato cobaltate (II) [HgCo(NCS)4] as a calibrant (χg = 16.44 × 10-6 cgs units at
20 °C). Diamagnetic corrections were made using Pascal’s constant.
2.1. General procedure for the synthesis of ligand (HAMPOTe)
The bidentate ligand 3-(((8-hydroxyquinolin-5-yl)amino)methyl)-5-phenyl1,3,4-oxadiazole-2(3H)-thione (HAMPOTe) was synthesized by condensation of 5phenyl-1,3,4-oxadiazole-2(3H)-thione with 5-amino-8-hydroxyquinoline hydrochloride
[25,26] (Scheme 1). Yield 78 %; LC/MS : 350.23; 1H NMR (δ ppm): 3.89 (d, 2H, -CH2-),
5.56 (t, 1H, -NH-), 6.52-7.84 (m, 10H, Ar-H), 9.87 (s, 1H, -OH, D2O exchangeable);
13C
NMR (δ ppm): 52.89, 109.23, 115.97, 118.04, 118.09, 123.02, 123.67, 123.82, 125.26,
125,82, 126.05, 126.43, 126.79, 167.62, 170.27.
Scheme 1
2.2. General procedure for the synthesis of metal complexes
A warm solution of metal(II) salt (2.5 mmol) in 50% aqueous formic acid (2.5
mL) was added dropwise with continuous stirring to previously warmed solution of
3
ligand (HAMPOTe) (5 mmol, 2 equiv.) in 20% aqueous formic acid solution (20
mL).With the proper adjustment of the pH (6-7) with 50% NH4OH, the resultant mixture
was further digested in a water bath for 4 - 5 h (Scheme 2). The suspended metal
complex collected by filtration, washed with distilled water and little hot ethanol then
finally dried in vacuum desiccators over anhydrous calcium chloride [26]. The physical
data of compounds are reported in Table 1. Yield 65-80 %; 1H NMR (δ ppm) for Zn+2
complex: 3.94 (d, 4H, -CH2-), 5.58 (t, 2H, -NH-), 6.42-8.23 (m, 20H, Ar-H);
13C
NMR: (δ
ppm): 54.75, 107.27, 117.97, 118.32, 118.84, 119.09, 120.21, 122.07, 123.03, 123.61,
124.82, 125.06, 125,81, 126.45, 126.93, 127.79, 169.00, 173.19.
Scheme 2
3.
Results and Discussion
The important infrared spectral bands of ligand (HAMPOTe) and its metal
complexes are summarized in Table 2. The ν (C–O), observed in the free oxine molecule
at around 1076 cm-1, shifted to higher frequencies in all the metal complexes, giving a
strong absorption band at 1149 cm-1 [27]. This clearly indicates the coordination of 54
amino-8-hydroxyquinoline in these complexes. The broad band at 3292 cm-1 observed
in the case of ligand was shifted at around 3375 cm-1, which was attributed to ν (O–H) of
coordinated water molecule. In the investigated metal complexes, the bands observed in
the region 3310-3335, 1260-1285, 865-875 and 710-715 cm-1 are attributed to –OH
stretching, bending, rocking and wagging vibrations respectively, due to the presence of
water molecules. The presence of rocking band indicates the coordination nature of the
water molecule [28]. Conclusive evidence of the bonding is also shown by the
observation that new bands in the IR spectra of the complexes appear at 525-484 cm-1
and 765 and 1425 cm-1 assigned to ν (M–O) and ν (M–N) stretching vibrations [29].
Structural analysis of the ligand (HAMPOTe) was carried out with the help of 1H and 13C
NMR using DMSO-d6 at room temperature. In case of 1H NMR spectrum of the ligand
(HAMPOTe), a broad singlet equivalent to one proton was observed at 9.87 δ ppm
corresponding to –OH group [30]. This signal disappeared when a D2O exchange
experiment was carried out. Aromatic protons observed at 6.52-7.84 δ ppm. In ligand
(HAMPOTe), –NH protons gave triplet at 5.56 δ ppm.
13C
NMR of ligand (HAMPOTe)
shows peaks at 14.55, 55.83 for aliphatic carbon and 111.51-151.44 for aromatic
carbon, and 158.90 for thione. By comparing the 1H NMR data of the ligand (HAMPOTe)
and the metal complex of Zn2+, it was concluded that the signal for –OH proton
disappears in case of complexes. Disappearance of this signal in case of Zn 2+ complex is
attributed to loss of proton due to coordination of oxygen atom with metal ion [31]. The
signal for adjacent proton attached to N of quinoline (H2) appeared at very low
magnetic field (9.00 δ ppm) compared with that of ligand (8.93 δ ppm), suggesting the
involvement of N in the complex formation. The –NH protons remain unaltered in the
spectrum of Zn2+ complex suggesting no involvement of this group in coordination.
The results of the magnetic moment value (Table 1) supported octahedral
geometry for all the metal complexes [32]. The antimicrobial activity data of all the
compounds are summarized in Table 3. The newly generated metal complexes have
exerted significant inhibitory activity against the growth of the tested bacterial and
fungal strains. The antimicrobial activity of metal complexes may be considered in light
of Overtone’s concept [33] and Tweedy’s chelation theory [34]. Investigation of
antimicrobial screening data reveals that almost all the compounds are active and
5
showing good antimicrobial activity. The Fe2+ and Cu2+ complexes exhibit comparable
activity to the standard drugs.
Table 1 Physicochemical parameters of the ligand (HAMPOTe) and metal complexes
Empirical formula of
ligand / metal
complexes
HAMPOTe
C17H13N5O2S
[Mn(HAMPOTe)2(H2O)2]
C34H28MnN10O6S2
[Fe(HAMPOTe)2(H2O)2]
C34H28FeN10O6S2
[Co(HAMPOTe)2(H2O)2]
C34H28MCoN10O6S2
[Ni(HAMPOTe)2(H2O)2]
C34H28NiN10O6S2
[Cu(HAMPOTe)2(H2O)2]
C34H28CuN10O6S2
[Zn(HAMPOTe)2(H2O)2]
C34H28ZnN10O6S2
Mole.
Weight
350.23
Colour
m.p.
(˚C)
990.30
989.29
991.35
993.34
μeff
calc. % (found %)
B.M.
C
Pale
yellow
273
Dark
Brown
Dark
Green
Dark
Red
Dark
Green
Dark
Yellow
>300
>300
>300
>300
>300
H
N
S
59.28 5.08 9.37 15.12
(59.30) (5.04) (9.34)(15.16)
57.83 4.23 8.73
986.30 Brown >300
987.30
Elemental Analysis
metal (calc.)
--
--
13.64 6.64
5.67
(57.80)(4.20) (8.70)(13.63) (6.61) (5.72)
57.75
4.26 8.78 13.60
6.78
5.34
(57.72) (4.24) (8.81)(13.62) (6.81) (4.98)
57.89
4.29 8.76 13.58
6.87
4.72
(57.87) (4.32) (8.73)(13.60) (6.90) (3.86)
57.77
4.25 8.74 13.67
6.89
3.20
(57.74) (4.28) (8.76)(13.65) (6.87) (2.72)
57.87
4.27 8.72 13.53
7.23
1.86
(57.82) (4.31) (8.70)(13.56) (7.25) (1.63)
57.74
4.26 8.73 13.49
7.10
Dia.
(57.76) (4.23) (8.76)(13.52) (7.14)
Table 2 FT-IR spectral frequencies of M(II)(HAMPOTe)2 (in cm-1)
Compound
ν(O–H)
ν(C=N)
ν(S=O)
[Mn(HAMPOTe)2(H2O)2]
3368(br)
1565
282
521
768
1423
1091
[Fe(HAMPOTe)2(H2O)2]
3373(br)
1567
286
525
767
1419
1096
[Co(HAMPOTe)2(H2O)2]
3377(br)
1575
283
522
763
1424
1092
[Ni(HAMPOTe)2(H2O)2]
3372(br)
1570
280
518
772
1421
1097
[Cu(HAMPOTe)2(H2O)2]
3376(br)
1579
285
524
770
1427
1089
[Zn(HAMPOTe)2(H2O)2]
3371(br)
1572
281
521
764
1420
1093
3292
1598
276
--
--
--
--
HAMPOTe
ν(N
M)
ν(N
M)
ν(O
M)
ν(C-O-M)
6
Table 3 Antimicrobial activities of studied compounds
Compound
Zone of inhibition, mma
S.aureus
B.subtillis
E.coli
P.aerugionsa
A.niger
A.flavous
5AHQ
24
22
26
22
21
19
HAMPOTe
32
33.5
30
29
37.5
34
[Mn(HAMPOTe)2(H2O)2]
16
12
14
14
13
11
[Fe(HAMPOTe)2(H2O)2]
23.5
21
23.5
20
24.5
22.5
[Co(HAMPOTe)2(H2O)2]
17
15.5
16
17.5
14
18
[Ni(HAMPOTe)2(H2O)2]
19.5
16
14
19
16
15
[Cu(HAMPOTe)2(H2O)2]
21
23.5
22
21
21.5
20
[Zn(HAMPOTe)2(H2O)2]
14.5
16
11
12.5
12
15
Sulphanilamide
18
14
20
19
24
22
Ciprofloxacin
28
42
26
35
44
38
a:
Results are taken in triplicate and average are shown.
4.
Conclusion
The
novel
3-(((8-hydroxyquinolin-5-yl)amino)methyl)-5-(phenyl-4-yl)-1,3,4-
oxadiazole-2(3H)-thione (HAMPOTe) and its octahedral metal(II) oxinates (1:2 metal to
ligand ratio) were synthesized and characterized. They showed good antibacterial and
antifungal activities compared to 5-amino-8-hydroxyquinoline (5AHQ). This might be
due to the additive biological effect of parent molecules and/or due to the metal chelating
properties. Among the oxinates, Fe(II) and Cu(II) chelates showed better activity
comparable to Ciprofloxacin, but were found less active than ligand (HAMPOTe).
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