Antibacterial, spectral, and thermal aspects of some [1,2,4-triazolo] [3,4-b][1,3,4]thiadiazine based heterochelates

Article abstract of DOI:10.1080/15533174.2011.555865

New ligands 5-((4-(3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine-6-yl)phenylamino)methyl)quinolin-8-ol (L₁) and 5-((3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6- ylamino)methyl)quinolin-8-ol (L₂) have been synthesized. The obtained ligands were characterized by ¹H NMR, ¹³C NMR, and IR spectroscopic techniques, and reacted with transition metal salts to afford metal containing heterochelates. The structures of the synthesized heterochelates were characterized using elemental analyses, infrared spectra, electronic spectra, magnetic measurements, FAB mass spectrum, and thermo gravimetric analyses. The kinetic parameters, such as order of reaction (n) and the energy of activation (Ea), are reported using the Freeman-Carroll method. Ligands and heterochelates were also screened for their in vitro antibacterial activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15533174.2011.555865

Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:315–328, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.555865
Antibacterial, Spectral, and Thermal Aspects of Some
[
1,2,4-triazolo] [3,4-b][1,3,4]thiadiazine Based
Heterochelates
Kaushal K. Oza, Darshan H. Jani, and Hasmukh S. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
attracted particular attention due to their diverse applications
New ligands 5-((4-(3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b] as antibacterial, antidepressant, antiviral, antitumoral, and anti-
[
5
1,3,4]thiadiazine-6-yl)phenylamino)methyl)quinolin-8-ol (L
-((3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-
1
) and inflammatory agents, pesticides, herbicides, lubricant, and an-
[14,15]
alytical reagents.
A number of triazoles fused to thiadi-
ylamino)methyl)quinolin-8-ol (L
obtained ligands were characterized by H NMR, C NMR, and
2
) have been synthesized. The
azines or thiadiazoles are incorporated into a wide variety of
therapeutically important compounds possessing a broad spec-
1
13
IR spectroscopic techniques, and reacted with transition metal
salts to afford metal containing heterochelates. The structures of trum of biological activities.[
15−18]
Hydroxyquinoline is a priv-
the synthesized heterochelates were characterized using elemental ileged structural moiety observed in many biologically active
analyses, infrared spectra, electronic spectra, magnetic measure-
ments, FAB mass spectrum, and thermo gravimetric analyses. The
versely prescribed among a wide range of pathologies includ-
kinetic parameters, such as order of reaction (n) and the energy of
activation (Ea), are reported using the Freeman–Carroll method.
Ligands and heterochelates were also screened for their in vitro disease,[ and herpes viral diseases.
antibacterial activity.
hydroxyquinoline moiety has been mostly used for its capacity
to strongly chelate metal ions, particularly Cu and Zn
Keywords 8-hyrdroxy quinoline, in vitro antibacterial activity, spec- 5-chlromethyl-8-quinolinol (CMQ) can be synthesized facilely
troscopy studies, thermal studies, thiadiazine
natural products, and is used as the source for many drugs di-
[19]
ing neurodegenerative diseases, parasitic amoebic dysentery
20]
[21]
More specifically, 8-
+2
+2 [22]
.
[23]
and studied extensively.
From our lab, it was previously re-
ported that CMQ clubbed benzotriazole derivatives and its metal
chelates give enhanced antimicrobial activity.[ Chelating lig-
ands 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.[ The presence of tran-
sition metals in human blood plasma indicates their importance
in the mechanism for accumulated storage and transport of tran-
sition metals in living organisms.[ Transition metals play a
key role in biological systems such as cell division, respiration,
nitrogen fixation, and photosynthesis.[
24]
INTRODUCTION
In recent decades, the construction of metal–organic coordi-
nation architectures has witnessed tremendous growth because
of their intriguing structures and potential properties.[1–4] Thia-
diazines are efficient antibacterial and antifungal compounds,[
and their use in the treatments of the bacterial helicobacter py-
lori and as reverse transcriptase inhibitors of the human immun-
25]
5]
26]
[
6,7]
26]
odeficiency virus have been reported.
It was reported that
the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines possess antimicro-
Looking to pharmaceutically importance of thiadiazine and
CMQ, the authors decided to synthesize ligand containing thia-
diazine and CMQ in one molecule. They may afford the com-
pound having not only the metal gripping potentiality, but may
also have good biological efficiency. Hence, the present arti-
cle describe the synthesis and characterization of a novel hete-
bial activity.[ The [1,2,4] triazoles are known for their broad
8]
spectrum of biological activities and many other uses.[
9−13]
The
synthesis of triazoles fused to another heterocyclic ring has
+2
+2
+2
+2
+2
rochelates, with Cu , Co , Ni , Mn and Zn metal ions.
Received 30 July 2010; accepted 1 October 2010.
The authors express gratitude to Department of Chemistry, Sardar
Patel University, Vallabh Vidyanagar, India for providing laboratory
facilities. Analytical facilities provided by the SAIF, Central Drug Re-
search Institute, Lucknow, India. One of the authors, Kaushal K. Oza,
is thankful to UGC New Delhi for providing scholarship.
Address correspondence to Hasmukh S. Patel, Department of
Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120, Gu-
jarat, India. E-mail: drhspatel786@yahoo.com
MATERIALS AND METHODS
Materials
The chemicals used for synthesis purpose were all of analyt-
ical grade, such as isoniazide, 8-hydroxy quinoline (purchased
315

316
K. K. OZA ET AL.
from local market), Luria broth and agar-agar (from SRL, In- under vacuum and the precipitate formed was filtered,
dia), metal(II)-salts (chloride/nitrate/sulfate) of Mn(II), Co(II), then washed with water. Dried crude product was taken
Ni(II), Cu(II), and Zn(II) were used in their hydrated form. Silica up with conc. HCl and was refluxed for 2 h. After cooling
gel F254 thin-layer chromatographic plates of size 20 × 20 cm in an ice bath, the mixture was neutralized with dilute
were purchased from the E. Merck (India) Limited, Mumbai and alkali. The solid (4-(3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-
used for purity evaluation. The organic solvents were purified b][1,3,4]thiadiazine-6-yl)aniline) obtained was filtered off
[27]
by the recommended method.
and air dried. To the mixture of 4-(3-(pyridine-4-yl)-7H-
1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-yl)aniline (8.00 g,
6.00 mmol) and triethylamine (8.18 g, 80.8 mmol) in dry
[
2
Instruments
pyridine (40 ml), CMQ (6.20 g, 26.90 mmol) was added with
continuous stirring. The contents were refluxed for 150 min.
The completion of the reaction was confirmed by TLC. The
excess of pyridine was distilled off and the residue was poured
into the ice-cold water to yield a light green product, which
was filtered and washed with hot water and then dried over a
vacuum desiccator. Yield, 71%; m.p., 183–185 C. Found (%):
C, 64.48, H, 4.12, N, 21.00. C25H19N7OS (465.00) requires
(%): C, 64.51, H, 4.08, N, 21.07. IR: 3293 (O H), 1642
The contents of carbon, hydrogen and nitrogen were ana-
lyzed with a Perkin Elmer, USA 2400-II CHN analyzer. The
metal contents of the heterochelates were analyzed by EDTA
titration after decomposing the organic matter with a mixture
of concentrated HClO4, H2SO4 and HNO3 (1: 1.5: 2.5).[28] The
melting points were checked by standard open capillary method
◦
−1
and were uncorrected. Infrared spectra (4000–400 cm ) were
recorded on Nicolet-400D spectrophotometer using KBr pel-
1
13
lets. H-NMR and C-NMR spectra were recorded on a model
Advance 400 Bruker FT-NMR instrument and DMSO-d6 used
as a solvent. The FAB mass spectrum of the heterochelate was
recorded at SAIF, CDRI, Lucknow with Jeol SX-102/DA-6000
mass spectrometer. The magnetic moments were obtained by
Gouy’s method using mercury tetrathiocyanato cobaltate (II) as
(
(
(
C N), 1502 (Ar C C), 3310, 3140 (N H), 1010 (N N), 689
C S C) ; H NMR: 9.82 (1H, s, protons OH), 6.70-8.82
1
13H, m, protons Ar), 6.50 (1H, t, N H), 4.33 (2H, s, protons
13
S CH2), 4.25 (2H, s, protons CH2); C NMR: 156.68,
53.82, 153.52, 150.79, 149.48, 148.56, 144.43, 138.98,
136.49, 133.81, 130.04, 129.27, 127.98, 122.24, 121.68,
19.36, 113.96, 111.77, 45.00, 22.69.
1
◦
a calibrant (g = 16.44 × 10−6 c.g.s. units at 20 C). Diamagnetic
1
corrections were made using Pascal’s constant. The reflectance
spectra of the ligands and their heterochelates were recorded in
the range 1700–350 nm (as MgO disks) on a Beckman DK-2A
spectrophotometer. A simultaneous · TG/DTG was obtained by 5-((3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
a model 5000/2960 SDT, TA Instruments, USA. The experi- thiadiazine-6-ylamino)methyl) quinolin-8-ol (L2)
ments were performed in an N2 atmosphere at a heating rate of
A mixture of 4-amino-5-(pyridine-4-yl)-4H-1,2,4-triazole-
0 C min in the temperature range 50–800 C, using an Al2O3 3-thiol (100 mmol), chloroacetonitrile (100 mmol) and sodium
◦
−1
◦
1
crucible. The sample sizes are ranged in mass from 5 to 8 mg.
acetate (490 mmol) in ethanol was heated under reflux for 6 h.
After cooling, the solvent was removed under reduced pressure
and the solid product (3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazine-6-amine) formed was washed with wa-
ter and air dried. To the mixture of 3-(pyridine-4-yl)-7H-
Synthesis of Ligand
The uninegative bidentate ligands L1 and L2 were synthe-
sized by condensation of 5-chloromethyl-8-hydroxyquinoline
hydrochloride (CMQ) and 4-(3-(pyridine-4-yl)-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine-6-yl)aniline and 3-(pyridine-
[
1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-amine (6.03 g, 26.00
mmol) and triethylamine (8.18 g, 80.8 mmol) in dry pyridine
40 ml), CMQ (6.20 g, 26.90 mmol) was added with continuous
(
4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-amine, re-
stirring. The contents were refluxed for 90 min. The completion
of the reaction was confirmed by TLC. The excess of pyridine
was distilled off and the residue was poured into the ice-cold
water to yield a light green product which was filtered and
washed with hot water and then dried over a vacuum desic-
spectively. CMQ was prepared and used as starting materials
for the synthesis of novel ligands L1 and L2 by slight modifica-
[23]
tion of the method reported in the literature, while metal(II)
heterochelates of L1 and L2 were synthesized by a subsequently
reported method.[
29]
◦
cator. Yield, 73%; m.p., 171–173 C. Found (%): C, 58.60, H,
5
-((4-(3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
3.89, N, 25.21. C19H15N7OS (389.00) requires (%): C, 58.61, H,
thiadiazine-6-yl)phenylamino) methyl)quinolin-8-ol (L1)
3.85, N, 25.19. IR: 3286 (O H), 1640 (C N), 1510 (Ar C C),
1
3
9
312, 3132 (N H), 1017 (N N), 690 (C S C) ; H NMR:
.89 (1H, s, protons OH), 6.72-8.80 (9H, m, protons Ar), 6.53
4
-amino-5-(pyridine-4-yl)-4H-1,2,4-triazole-3-thiol
was
[30]
prepared according to reported method.
A mixture of
(
1H, t, N H), 4.32 (2H, s, protons S CH2), 4.20 (2H, s, pro-
N-(4-(2-chloroacetyl)phenyl)acetamide (100 mmol) and 4-
amino-5-(pyridine-4-yl)-4H-1,2,4-triazole-3-thiol (100 mmol)
and sodium acetate (250 mmol) in absolute ethanol was
refluxed for 2 h. After cooling, the solvent was removed
13
tons CH2); C NMR: 156.80, 153.77, 152.51, 149.12, 148.32,
1
1
43.98, 138.30, 136.40, 133.80, 129.20, 127.98, 121.20, 119.30,
18.20, 111.70, 44.00, 22.60.

THIADIAZINE BASED HETEROCHELATES
317
General Procedure for the Synthesis of Heterochelates
incomplete removal of 8-hydroxyquinoline. The possibility of
A warm solution of metal(II) salt (2.5 mmol) in 50% aqueous substitution reaction during the crystallization with protic sol-
formic acid (2.5 ml) was added drop by drop with continuous vent was prevented by avoiding the use of inorganic base cat-
stirring to previously warmed solution of ligand (5 mmol, 2 alyst such as sodium/potassium bicarbonate, sodium/potassium
equivs) in 20% aqueous formic acid solution (20 ml). With the hydrogen carbonate, and sodium hydroxide. An earlier report
proper adjustment of the pH (6–7) with 50% NH4OH, the resul- shows resultant slow reaction or presence of 5-hydroxymethyl-
tant mixture was further digested in a water bath for 4–5 h and 8-hydroxyquinoline in quantitative yield.[ To overcome such
centrifuged. The suspended solid complex was allowed to settle discrepancies, triethylamine (TEA) was used as scavenger while
and collected by filtration, washed with sufficient quantity of reacting CMQ with 4-(3-(pyridine-4-yl)-7H-[1,2,4]triazolo[3,4-
distilled water and then with a little hot ethanol and acetonitrile, b][1,3,4]thiadiazine-6-yl)aniline and 3-(pyridine-4-yl)-7H-
then dried in vacuum desiccators over anhydrous calcium chlo- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-amine to afford good
ride. The physical data of ligand and heterochelates are shown yield. The synthesized novel ligands L1 and L2appear as light
32]
in Table 1.
green crystals. It has partial solubility in acetone, methanol,
ethanol, and acetonitrile, while being soluble in polar a
protic solvents like dimethylformamide (DMF), dimethyl-
sulfoxide (DMSO), organic acids, and pyridine. All the
Bio Assay: Zone of Inhibition Technique
Preparation of Stock Solution
A stock solution of 10 mg ml 1 was made by dissolving
compound in minimum amount of DMSO and making it up to
the mark with double distilled water.
[
M(II)(L1)2(H2O)2] and [M(II)(L2)2(H2O)2] had characteristic
−
color, are stable in air, and practically insoluble in water, ethanol,
methanol, chloroform, and hexane.
IR Spectra
Preparation of Agar Plates
The important infrared spectral bands and their tentative as-
signments for the synthesized heterochelates were recorded
as KBr disks and are summarized in Table 2. In the 8-
hydroxyquinoline complexes of divalent metals, the υ(C O),
The media was made up by dissolving bacteriological agar
(
20 g) and Luria broth (20 g) (SRL, India) in 1 l distilled water.
◦
The mixture was autoclave for 15 min at 120 C and then dis-
pensed into sterilized Petri dishes, allowed to solidify, and then
used for inoculation.
−1
appeared at 1120 cm region and the position of the band
slightly varies with the metal.[ The υ(C O), observed in the
33]
−1
Procedure of Inoculation
ligands molecule at 1082(L1),1089(L2) cm , shifted to higher
frequencies in all the hetero chelates, giving a strong absorption
The target microorganism cultures were prepared separately
in 15 ml of liquid Luria broth medium for activation. Inoculation
was done with the help of micropipette with sterilized tips;
−1
band at 1159–1189 cm . This clearly indicates the coordi-
nation of 8-hydroxyquinoline in these complexes. The broad
−
1
band at 3293(L1), 3287 (L2) cm observed in the case of lig-
1
00 µl of activated strain was placed onto the surface of an agar
−1
ands was shifted in all heterochelates at ∼3321 cm , which
was attributed to υ(O H) of coordinated water molecule. In
the investigated heterochelates, the bands observed in the re-
plate, and spread evenly over the surface by means of a sterile,
bent glass rod. Then two wells having diameter of 10 mm were
made using a sterilized borer in each plate.
−1
gion 3311–3331, 1272–1293, 866–879, and 708–715 cm are
attributed to OH stretching, bending, rocking and wagging vi-
brations, respectively, due to the presence of water molecules.
The presence of rocking band indicates the coordination nature
of the water molecule.[ Coordinated water were further sup-
ported by TG analysis. The υ(C N) observed in the ligands
Application of Disks
Sterilized stock solutions (10 mg ml−1) were used for the
application in the well of earlier inoculated agar plates. When
34]
◦
the disks were applied, they were incubated at 30 C (Gram-
◦
positive) and 37 C (Gram-negative) for 24 h. The zone of inhi-
−
1
and heterochelates at ∼1642 cm . The υ(N H) observed at
bition was then measured (in mm) around the disk. The control
experiments were performed with only the equivalent volume
of solvents without added test compounds and the zone of inhi-
bitions was measured (in mm). All experiments were performed
∼
3310, ∼3140 in the ligands and heterochelates. The υ(N N)
observed at ∼1010, υ(C S C) at ∼689, and which were at-
tributed to thiadiazine ring in ligands and heterochelates.[
35]
−1
in triplicate, and ciprofloxacin was used as the standard drug.[
31]
In the far-IR region, two new bands at ∼504 and ∼531 cm
in the heterochelates were assigned to υ(M O) and υ(M N),
respectively.[ All of these data confirm the fact that ligands
L1and L2 behaves as uninegative bidentate.
36]
RESULTS AND DISCUSSION
5-Chloromethyl-8-hydroxyquinoline hydrochloride was pre-
pared by chloromethylation of 8-hydroxyquinoline. Consider-
able difficulties were faced while obtaining high purity of CMQ
even after washing the crude product with concentrated hy-
1H- and 13C-NMR Spectra
Structural analysis of the ligands were carried out with
1
13
drochloric acid and acetone, which may have been caused by the help of H- and C-NMR using DMSO-d6 at room

318

THIADIAZINE BASED HETEROCHELATES
319
TABLE 2
The characteristic IR bands of ligands and their heterochelates
Compounds υ(O H) cm 1 υ(C N) cm
−
−1
υ(C S C) cm
−1
υ(C O) cm
−1
υ(N N) cm
−1
υ(M O) cm
−1
−1
υ(M N) cm
L1
L2
1
2
3
4
5
6
7
3293 (br)
3287 (br)
3311 (br)
3323 (br)
3331 (br)
3318 (br)
3323 (br)
3327 (br)
3323 (br)
3329 (br)
3317 (br)
3319 (br)
1642 (w)
1648 (w)
1643 (w)
1642 (w)
1637 (w)
1640 (w)
1639 (w)
1647 (w)
1639 (w)
1643 (w)
1632 (w)
1642 (w
689 (s)
690 (s)
682 (s)
694 (s)
685 (s)
681 (s)
694 (s)
681 (s)
684 (s)
691 (s)
682 (s)
693 (s)
1082 (m)
1089 (m)
1159 (m)
1189 (m)
1177 (m)
1164 (m)
1181 (m)
1167 (m)
1172 (m)
1179 (m)
1183 (m)
1188 (m)
1010 (m)
1018 (m)
1020 (m)
1017 (m)
1004 (m)
1009 (m)
1013 (m)
1014 (m)
1008 (m)
1012 (m)
1019 (m)
1017 (m)
—
—
—
—
504
507
509
510
519
510
508
517
503
507
531
537
547
549
534
539
532
534
543
546
8
9
10
s=strong, m=medium, w=weak, br=broad, m= metal
temperature. The data are presented in the Experimental sec-
tion. In the case of H-NMR spectra for the ligands, one broad
(
L1), 6.53 (L2) δ ppm triplet was observed, equivalent to one
1
proton corresponding to N H. At 4.33 (L1), 4.32 (L2) δ ppm
singlet was observed, equivalent to two protons corresponding
to S CH2of thiadiazine ring. Another singlet was observed,
singlet equivalent to one proton was observed at 9.82 (L1),
[37,38]
9.89 (L2) δ ppm corresponding to O H group.
This sig-
nal disappeared when a D2O exchange experiment was car-
ried out. For the ligand L1 in the region of 6.70–8.82 δ ppm,
multiplate were observed, equivalent to thirteen protons cor-
responding to aromatic protons. For the ligand L2 in the re-
gion of 6.72–8.80 δ ppm, multiplate were observed, equiva-
lent to nine protons corresponding to aromatic protons. At 6.50
equivalent to two protons corresponding to CH2 at 4.25 (L1),
1
4.20 (L2) δ ppm. By comparing the H-NMR data of the lig-
ands and the Zn(II) heterochelate, it was concluded that the sig-
nal for OH proton disappears in case of Zn(II) heterochelate.
Disappearance of this signal in case of Zn(II) heterochelate is
attributed to loss of proton due to coordination of oxygen atom
FIG. 1. Proposed structures of heterochelates.

320
K. K. OZA ET AL.
FIG. 2. Freeman-Carroll plot for the heterochelate [Cu(L1)2(H2O)2].
with metal ion.[39] The signal for adjacent proton attached to carbons were observed at 45.00, 22.69 ppm. In C-NMR spectra
N of quinoline appeared at very low magnetic field compared of L2, peaks observed at 156.80, 153.77, 152.51, 149.12, 148.32,
with that of ligand, suggesting the involvement of N in the 143.98, 138.30, 136.40, 133.80, 129.20, 127.98, 121.20, 119.30,
l3
1
heterochelate formation. In the H NMR spectra of Zn(II) hete- 118.20, and 111.70 δ ppm were assigned to aromatic carbons.
rochelates, all other signals that remain unaltered as compared Aliphatic carbons were observed at 44.00, 22.60 ppm.
with ligands suggest non involvement of this groups.
l3
In C-NMR spectra of L1, peaks observed at 156.68, 153.82,
53.52, 150.79, 149.48, 148.56, 144.43, 138.98, 136.49, 133.81,
30.04, 129.27, 127.98, 122.24, 121.68, 119.36, 113.96, and
11.77 δ ppm were assigned to aromatic carbons. Aliphatic [Cu(L2)2(H2O)2] exhibited two bands, at 26238 cm and 26247
Diffuse Electronic Spectral and Magnetic Properties Data
1
1
1
The diffuse electronic spectra of [Cu(L1)2(H2O)2],
−1
FIG. 3. FAB Mass spectrum for the heterochelate [Cu(L1)2(H2O)2].

THIADIAZINE BASED HETEROCHELATES
321
TABLE 3
Thermoanalytical results (TG, DTG) of the heterochelates
◦
◦
Compounds TG range/ C DTG max/ C Mass loss % Obs.(calcd.)
Assignment
1
2
3
4
5
6
7
8
9
1
120–210
189
293
679
3.51(3.50)
50.15
40.16
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving CuO
residue.
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving CoO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving NiO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving MnO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving ZnO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving CuO
residue.
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving CoO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving NiO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving MnO
residue
Loss of two coordinated water molecules
Removal of some part of ligand
Removal of remaining part of ligand leaving ZnO
residue
2
4
10–453
53–800
134–205
187
—
648
3.49(3.51)
52.55
38.16
2
4
05–443
43–800
124–209
176
310
603
3.50(3.52)
55.77
34.96
2
4
09–449
49–800
125–200
183
402
697
3.55(3.53)
49.71
41.36
2
4
00–451
51–800
122–205
151
—
689
3.47(3.49)
52.56
37.59
2
4
05–442
42–800
125–189
154
317
543
4.14(4.11)
49.77
38.86
1
4
89–410
10–800
127–183
162
298
678
4.12(4.13)
51.54
37.56
1
4
83–403
03–800
117–185
169
323
643
4.15(4.13)
49.93
39.19
1
4
85–413
13–800
118–191
149
353
—
4.13(4.15)
52.56
36.95
1
4
91–407
08–800
0
128–192
178
—
590
4.12(4.10)
48.63
39.81
1
4
92–412
12–800
−
1
−1
cm , respectively, due to charge transfer and a broad band three weak absorption bands at 9974, 16013, and 24464 cm
,
−1
−1
−1
having maxima at 1558 cm and 1567 cm , respectively, due 9969, 16000, and 24434 cm , respectively, corresponding to
2
2
3
3
3
3
to the Eg → T2g transition. The broadening of the signal might the characteristic transitions A2g → T2g, A2g → T1g(F),
3
3
be due to Jahn–Teller distortion. The absorption bands of the
A2g → T1g(P). [Co(L1)2(H2O)2], [Co(L2)2(H2O)2] exhibited
−
4
1
diffuse electronic spectra and the value of their magnetic mo- three absorption bands at 9828, 15481, and 22107 cm , 9813,
−1
4
ment favor a tetragonally distorted octahedral geometry around 15460, and 22110 cm , respectively, due to T1g(F) → T2g(F),
Cu(II) ion.[
40−42]
[Ni(L1)2(H2O)2], [Ni(L2)2(H2O)2] showed
4
T1g(F) → A2g(F) and T1g(F) → T1g(P) transitions. The
4
4
4

322
K. K. OZA ET AL.
TABLE 4
Thermodynamic data of the thermal decomposition of heterochelates
◦
−1
−1
∗
−1
−1
∗
−1
∗
−1
Compounds TG range/ C Ea/kJ mol
n
A/s
S /JK mol
H /kJ mol
G /kJ mol
1
2
3
4
5
6
7
8
9
1
120–210
11.55
13.36
14.25
3.31
14.63
27.57
3.09
10.18
30.59
3.11
0.99
1.00
0.98
0.98
0.98
1.00
1.00
0.99
9.46
1.65
0.89
0.22
1.05
2.23
0.05
0.21
−96.72
−97.64
−99.72
−100.05
−99.00
−97.01
−102.32
−100.24
−95.86
−101.48
−100.42
−96.20
−100.11
−99.24
−95.86
−96.74
−97.64
−99.75
−100.10
−99.03
−97.00
−102.22
−100.44
−95.76
−101.89
−100.34
−96.10
−100.21
−99.14
−95.36
9.52
10.04
11.02
0.76
42.62
60.54
72.45
32.66
66.57
102.84
42.32
61.84
89.26
32.43
57.57
106.38
39.34
58.89
94.26
42.68
60.51
72.49
32.61
66.53
102.74
42.31
61.86
89.22
32.47
57.52
106.39
39.33
58.87
94.23
2
4
10–453
53–800
134–205
2
4
05–443
43–800
9.79
20.41
−0.22
5.43
25.08
0.34
2.36
26.86
0.23
2.24
26.75
9.32
10.03
11.01
0.74
124–209
2
4
09–449
49–800
1.00 19.53
125–200
1.00
1.00
0.98
0.98
1.00
0.99
0.99
0.98
1.00
0.99
0.99
1.00
0.99
0.99
0.11
0.10
8.25
0.13
0.25
5.22
9.43
1.68
0.81
0.23
1.00
2.22
0.04
0.22
2
4
00–451
51–800
6.08
33.69
3.11
122–205
2
4
05–442
42–800
6.10
33.72
11.54
13.35
14.26
3.34
14.69
27.51
3.10
10.20
30.61
3.19
6.12
33.72
3.13
125–189
1
4
89–410
10–800
127–183
1
4
83–403
03–800
9.72
20.44
−0.21
5.47
25.07
0.37
2.34
26.88
0.24
117–185
1
4
85–413
13–800
1.00 19.43
118–191
1.00
0.98
1.00
0.99
1.00
0.98
0.19
0.18
8.24
0.12
0.24
5.19
1
4
91–407
08–800
0
128–192
1
4
92–412
12–800
6.13
33.70
2.21
26.65
absorption bands of the diffuse electronic spectra and values of Thermal Response of Synthesized Heterochelate
their magnetic moments show an octahedral geometry around
The thermal behavior of the heterochelates was determined
[43,44]
Ni(II) and Co(II) ions.
The spectra of [Mn(L1)2(H2O)2], using a 5000/2960 SDTA, TA instrument (USA) differential
◦
[
2
Mn(L2)2(H2O)2] showed weak bands at 16776, 18421, and thermal analysis apparatus operating at a heating rate of 10 C
−
1
−1
◦
3807 cm , 16766, 18431, and 23812 cm , respectively, per minute in the range of 50–800 C in N atmosphere. Secu-
2
6
4
6
4
6
4
assigned to the A1g → T1g, A1g → T2g, A1g → A1g, ritization of this data envisages that all heterochelates follows
4
Eg transitions and their magnetic moment values suggest an three-step thermal decomposition. Each decomposition process
octahedral geometry for the Mn(II) ion. As the spectrum of follows the trend given below in scheme. This process comprises
[
Zn(L1)2(H2O)2], [Zn(L2)2(H2O)2] was not well resolved, it of several stages. The method reported by Freeman–Carroll
was not well interpreted, but its magnetic moment value shows method [ has been adopted. Plots of [ꢀlog(dw/dt)/ꢀlog wr]
46]
[29]
that it is diamagnetic in nature, as expected.
The results of vs. [ꢀ(1/T)/ꢀlog wr] were linear for all of the decomposition
the magnetic moment value (Table 1) were shown to have octa- steps. The energy of activation Ea was calculated from the slopes
hedral geometry for all the Hetero chelates. Hence, the observed of these plots for a particular stage and the order of reactions (n)
values of magnetic moments and the electronic spectra of hetero determined from the intercept, showing first order reaction over
chelates supported octahedral geometry for all the structures.[
45]
the entire range of decomposition for all of the heterochelates.
Probable structure of the complexes from the above analytical A typical Freeman–Carroll plot for the thermal degradation of
facts is given below in Figure 1.
[Cu(L ) (H O) ] is shown in Figure 2.
1
2
2
2

THIADIAZINE BASED HETEROCHELATES
323
The thermal fragmentation scheme for heterochelates
TABLE 5
[
M(Ln)2(H2O)2] is as shown in Scheme 1:
In vitro activity data of ligands and heterochelates
Zone of inhibition (mm)
Bacillus Staphylococcus Escherichia Serratia
Compounds
subtilis
aureus
coli
marcescens
Ciprofloxacin
33
11
12
30
19
21
15
18
29
13
19
18
17
39
13
09
36
21
25
17
16
32
19
22
15
20
38
14
08
33
18
26
11
20
31
21
28
18
21
44
12
10
36
20
26
19
15
32
18
24
13
16
L
L
1
2
1
2
3
4
5
6
7
8
9
SCH. 1.
In the first decomposition step, the weight loss during 117– 10
◦
2
10 C corresponds to two coordinated water molecules. A loss
in weight observed in the second step was corresponding to
the decomposition and combustion of some part of ligand in with peak at m/z 834 with loss of one coordinate H2O molecule
◦
the temperature range 183–453 C. The third subsequent stage and C10H8N2 moieties. Species (c) further degrades with the
for heterochelates shows the decomposition and combustion loss of C4H3N4S moieties forming species (d) with a peak at
of remaining part of ligand. The removal of ligand undergoes m/z 697. Species (d) further degrades with loss of C4H3N4S
decomposition forming MO as the final residue.
and C7H8N forming species (e). The sharp peak (base peak)
The thermodynamic activation parameters of the decompo- observed at m/z 454 represents the stable species (e) with 99.0%
sition process of dehydrated heterochelates such as activation abundance. Species (e) further degrades with loss of C6H6N
entropy (S*), pre-exponential factor (A), activation enthalpy forming species (f) at m/z 363. Species (f) further degrades with
(
H*) and free energy of activation (G*), were calculated using loss of C9H6N and CuO forming species (g).The measured
[47]
the reported equations.
According to the kinetic data ob- molecular weights for all the suggested degradation steps were
tained from DTG curves, all the heterochelates have negative consistent with expected values.[
50]
entropy, which indicates that the studied heterochelates have
[48]
more ordered systems than reactants.
The kinetic parame-
Antimicrobial Screening
Zone of Inhibition
ters, especially energy of activation (Ea) is helpful in assigning
the strength of the bonding of ligand moieties with the metal ion.
The calculated Ea values of the investigated heterochelates for
the degradation stage of ligand are in the range 3.09–33.72 kJ
The increase in antimicrobial activity may be considered in
light of Overtone’s concept and Tweedy’s chelation theory. Ac-
cording to Overtone’s concept of cell permeability, the lipid
membrane surrounding the cell favors the passage of lipid-
soluble materials making the solubility an important factor con-
trolling the antimicrobial activity. On chelation, the polarity of
the metal ion will be reduced to a greater extent due to the
overlap of the ligand orbital and partial sharing of the positive
charge of the metal ion with donor groups. Further, it increases
the delocalization of π-electrons over the whole chelate ring and
enhances the lipophilicity of the heterochelates. The increased
−1
mol . The relative high Ea value indicates that the ligand is
[49]
strongly bonded to the metal ion. From the above discussion,
an octahedral geometry of the heterochelates can tentatively be
assumed as shown in Figure 1. Thermoanalytical and thermo-
dynamic data of heterochelates are reported in Tables 3 and 4,
respectively.
FAB Mass Spectra
The recorded FAB mass spectrum (Figure 3) and the molec- lipophilicity enhances the penetration of the heterochelates into
ular ion peak for the heterochelate [Cu(L1)2(H2O)2] were used lipid membranes and blocks the metal binding sites in the en-
to confirm the molecular formula. The proposed fragmentation zymes of microorganisms. These heterochelates also disturb
pattern is shown in Scheme 2. The first peak at m/z 1027 rep- the respiration process of the cell and block the synthesis of
resents the molecular ion peak of the heterochelate. Scheme 2 proteins, which actually restricts further growth of the organ-
demonstrates the possible degradation pathway for the inves- isms. Furthermore, the mode of action comprising the com-
tigated heterochelate. The primary fragmentation of the hete- pounds may involve the formation of hydrogen bond through
rochelate takes place due to the loss of one coordinated H2O the azomethine/carbonyl/amine group with the active center of
molecule from the species (a) to give species (b) with peak at cell constituents and interferences are forced with the normal
m/z 1008. The species (b) further degrades to give species (c) cell process.[
31,51,52]

324
K. K. OZA ET AL.
SCH. 2. The suggested fragmentation pattern of compound 1.

THIADIAZINE BASED HETEROCHELATES
325
SCH. 2. (Continued)
It was observed that all the heterochelates were proven to applications in various fields of human interest. The nature of a
be more potent bacteriostatic compared to ligands, while Cu(II) coordination compound depends on the metal ion and the donor
heterochelate is highly active against all the organism among the atoms, as well as on the structure of the ligand and the metal–
heterochelates of the respective metal. Heterochelates exhibit ligand interaction.[53,54] Metal ions play a vital role in a vast
different characteristic properties, which depend on the metal number of different biological processes through co-enzymatic
ion to which they are bound, the nature of the metal as well as the systems. The interaction of these ions with biologically active
type of ligand, etc. These heterochelates have found extensive ligands, for instance in drugs, is a subject of great interest. Some

326
K. K. OZA ET AL.
biologically active compounds act via chelation, but for most of
them little is known about how metal coordination influences
their activity. This may support the argument that some type of
bimolecular binding to the metal ions or intercalation or electro-
static interactions causing the inhibition of biological synthesis
and preventing the organisms from reproducing. The strong
antimicrobial activities of these compounds against tested or-
ganisms suggest further investigation on these compounds. The
antimicrobial activity data of the compounds are summarized in
Table 5.
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CONCLUSIONS
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1
13
fully been demonstrated by FT-IR, H-NMR, and C-NMR
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