Thermal behaviour of new N,N-dimethylbiguanide complexes having selective and effective antibacterial activity

Article abstract of DOI:10.1007/s10973-005-7177-7

The complexes of the type M(HDMBG)₂(CH₃COO) ₂?nH₂O ((1) M:Mn, n=1.5; (2) M:Ni, n=0; (3) M:Cu, n=2; (4) M:Zn, n=2; DMBG: N,N-dimethylbiguanide) present in vitro antimicrobial activity. The thermal analysis has evidenced the thermal intervals of stability and also the thermodynamics effects that accompany them. The different nature of the ligands generates a different thermal behaviour for the complexes. The thermal transformations are complex processes according to TG and DTG curves including dehydration, oxidative condensation of -C=N- units as well as thermolysis processes. The final products of decomposition are the most stable metal oxides.

Full text of DOI:10.1007/s10973-005-7177-7

Journal of Thermal Analysis and Calorimetry, 84 (2006) 1, 53–58
THERMAL BEHAVIOUR OF NEW N,N-DIMETHYLBIGUANIDE
COMPLEXES HAVING SELECTIVE AND EFFECTIVE
ANTIBACTERIAL ACTIVITY
*
Rodica Olar , Michaela Badea, E. Cristurean, C. Parnau and D. Marinescu
University of Bucharest, Faculty of Chemistry, Department of Inorganic Chemistry, 90-92 Panduri Street
050663 Sector 5, Bucharest, Romania
2 3 2 2
The complexes of the type M(HDMBG) (CH COO) ·nH O ((1) M:Mn, n=1.5; (2) M:Ni, n=0; (3) M:Cu, n=2; (4) M:Zn, n=2;
DMBG: N,N-dimethylbiguanide) present in vitro antimicrobial activity. The thermal analysis has evidenced the thermal intervals of
stability and also the thermodynamics effects that accompany them. The different nature of the ligands generates a different thermal
behaviour for the complexes. The thermal transformations are complex processes according to TG and DTG curves including dehy-
dration, oxidative condensation of –C=N– units as well as thermolysis processes. The final products of decomposition are the most
stable metal oxides.
Keywords: complexes, N,N-dimethylbiguanide, paracyanide, thermal behaviour
Introduction
characterised as mononuclear species. These com-
pounds show also a good antimicrobial activity con-
cerning both the selectivity and the efficacy [16]. In
the last years these kinds of complexes were studied
in order to be included in a polymeric matrix either by
dispersion or by direct polycondensation with suit-
able organic monomers. The physico-chemical and
structural data indicate that in all complexes
N,N-dimethylbiguanide adopts a structure with two
It is well known that biguanide derivatives exhibit both
biological and coordinative properties [1]. Among
biguanide drugs, the most widely prescribed type II dia-
betes medications is N,N-dimethylbiguanide known as
Metformin [2]. Beside decreasing the glucose level, the
N,N-dimethylbiguanide also acts as analgesic, antima-
larial and antimetabolite for organisms that inhibit the
metabolism of folic acid [3, 4]. Recently, it was found
that platinum(IV) complex with N,N-dimethyl- bigu-
anide shows antitumor activity [5]. Attempting to mod-
ulate the biological activity of this derivative it was de-
monstrated that some of their complexes possess
antimicrobial activity and also have an interesting ther-
mal behaviour [6].
2
4
imine groups acting as chelate through N and N
imine atoms. In these conditions, each ligand possess
one amine uncoordinated group, that could be in-
volved in polycondensation processes. These groups
are also able to generate hydrogen bonding, which
play a very important role in the interactions with
biomolecules. These characteristics recommend this
type of complexes as good monomeric precursors for
biopolymers. Considering that the condensation pro-
cesses usually occur at higher temperatures, the ther-
mal behaviour of these derivatives was investigated in
order to evidence the thermal intervals of stability, the
thermodynamics effects that accompany them and to
correlate these with the structural aspects. The para-
cyanide formation after acetate degradation was ob-
served. The final residues are the metallic oxides as
X-ray diffraction indicates. The intermediate products
such as anhydrous complexes as well as carbonate
and some paracyanide species formed during thermo-
lysis were isolated and characterised.
Even if there are a rather small number of com-
plexes with N,N-dimethylbiguanide fully character-
ised, there was evidenced a versatile coordination
mode. Thus, it was shown that it could coordinate as
3
unidentate through N atom in a cationic form [7, 8],
2
4
as (N ,N ) chelate both in neutral as well as in anionic
form [9–13] and also it can be found in some com-
plexes as a discrete cation [14, 15]. The main direc-
tions of these studies consisted in determination of the
structure for these complexes [1].
Using this ligand, a series of new complexes of
type M(DMBG) (CH COO) ·nH O (M:Mn, n=1.5;
2 3 2 2
M:Ni, n=0; M:Cu, n=2 and M:Zn, n=2; DMBG:
N,N-dimethylbiguanide) have been synthesised and
*
Author for correspondence: rodica_olar@yahoo.co.uk
1
388–6150/$20.00
Akadémiai Kiadó, Budapest, Hungary
Springer, Dordrecht, The Netherlands
©
2006 Akadémiai Kiadó, Budapest

OLAR et al.
Experimental
All reagents were of commercial analytical quality
and have been used without further purification. The
new complexes were synthesised and previously
characterised by chemical analysis, electronic, IR and
EPR spectra. The redox behaviour was characterised
by voltammetric study and the biological assay were
performed by microdilution method [16].
Scheme 1
The chemical analysis and IR spectral data were
used in order to confirm the nature of some intermedi-
ates and also the final products. Chemical analysis of
carbon and nitrogen has been performed using an EA
albicans and Escherichia coli) as well as Candida.
The values of minimum inhibitory concentration re-
vealed for complex (2) a very good activity against
Listeria monocytogenes [16].
1
110 analyzer. Manganese, nickel, copper and zinc
were determined gravimetrically in the laboratories of
Inorganic Chemistry Department.
The major goal of this paper was to evidence the
thermal behaviour of these complexes that present in
vitro a very good antibacterial activity in order to pro-
cess these compounds as polymeric materials.
IR spectra were recorded in KBr pellets with a
Bio-Rad FTIR 135 spectrometer in the range
–
1
4
00–4000 cm .
The heating curves (TG, DTA and DTG) were
Thermal behaviour of complexes
recorded in a static air atmosphere using a MOM (Bu-
dapest) derivatograph, type Paulik-Paulik-Erdey,
with a sample mass between 43–100 mg over the tem-
perature range of 20–1000ºC, using a heating rate of
The results concerning the thermal decomposi-
tion/degradation of the complexes are presented in the
following.
–
1
1
0°C min .
Thermal decomposition of
[
Mn(C
4
H
11
N
5
)
2
(CH
3
COO)
2
]·1.5H
2
O
(1)
Results and discussion
The TG, DTG and DTA curves corresponding to
the complex (1) heated in the 20–1000ºC temperature
range are presented in Fig. 1.
The thermal decomposition occurs in three steps.
The first step with the maximum rate at 90ºC corre-
In this paper, it is reported the thermal behaviour of
some complexes with N,N-dimethylbiguanide
(
DMBG, C H N ) of type:
4 11 5
[
Mn(C H N ) (CH COO) ]·1.5H O
2
(1)
(2)
(3)
(4)
4
11 5 2
3
2
[
Ni(C H N ) ](CH COO)
4 11 5 2 3 2
[
Cu(C H N ) (CH COO) ]·2H O
4 11 5 2 3 2 2
[
Zn(C H N ) (CH COO) ]·2H O
2
4
11 5 2
3
2
These compounds were obtained by direct reac-
tion between metal acetates and N,N-dimethyl-
biguanidium nitrate in ethanol. It is important to men-
tion that physico-chemical studies had evidenced, that
with the Ni(II) exception that adopts a square planar
stereochemistry, the other metallic ions have an octa-
hedral surroundings. In all complexes the
N,N-dimethylbiguanide acts as chelate while the ace-
tate acts as unidentate ligand in all complexes except
for complex (2) where it is found as free ion. On the
basis of these data the following structures were
proposed for complexes (Scheme 1).
Antibacterial activity of the complexes has been
carried out against Gram positive and Gram negative,
reference and clinical strains (Bacillus subtilis, Pseu-
domonas aeruginosa, Staphylococcus aureus, Salmo-
nella enteritidis, Listeria monocytogenes, Candida
Fig. 1 TG, DTG and DTA curves of
[Mn(C H N ) (CH COO) ]·1.5H O
4
11 5 2
3
2
2
54
J. Therm. Anal. Cal., 84, 2006

N,N-DIMETHYLBIGUANIDE COMPLEXES AND THEIR ANTIBACTERIAL ACTIVITY
sponds to a dehydration process and it is accompanied
by a weak endothermic effect. The interval of this trans-
formation corresponds to presence of water in the lattice
of compound as also the IR spectrum indicates (Fig. 2a).
The second step, accompanied by a strong
exothermal effect, corresponds to manganese oxida-
tion and the acetate decomposition leading to the car-
bonate complex of bis(N,N-dimethylbiguanide) oxo-
dimanganese(III). These transformations are consis-
tent with the IR spectrum of the intermediate isolated
at 180ºC (Fig. 2b).
–
1
At 1384 (n
n3) appeared new bands that can be assigned to
unidentate carbonate [17] while the bands at 615 and
1 2 8
), 1064 (n ), 820 (n ) and 792 cm
(
–
1
5
15 cm are assigned to n (Mn–O–Mn) and
as
ns(Mn–O–Mn) [18] for the Mn(III)OMn(III) core
formed by manganese oxidation. Such behaviour was
also observed for other metal acetates [19]. From
2
00ºC the oxidative degradation of the DMBG starts
and at 450ºC this process is finished with the Mn O
4
3
formation. In this temperature interval at least three
chemical processes can be evidenced. By increasing
the temperature, the oxidative degradation of DMBG
is accompanied by the development of the layered
network of paracyanide as it is depicted in Scheme 2.
The alternatively coordinated –C=N– bonds assure
the optimal condition of the paracyanide network de-
velopment. This behaviour it was observed for other
complexes with ligands derived from DMBG [6, 20].
The black intermediate isolated at 400ºC shows an
4 11 5 2 3 2 2
Fig. 2 IR spectra of a – [Mn(C H N ) (CH COO) ]·1.5H O
and the intermediates at b – 180ºC and c – 390ºC re-
sulted from thermal degradation
–1
IR spectrum with band at 1537 cm assigned to n(C=N)
Thermal decomposition of
[Ni(C H N ) ](CH COO) (2)
–1
(Fig. 2c). The intense bands at 606 and 498 cm are
consistent with the spinelic lattice of Mn O [21].
4
11 5 2
3
2
3
4
The anhydrous nature of complexes is reflected by the
fact that thermal decomposition starts at 315ºC, and
unlike the other complexes of the series the melting
was observed at a higher temperature (Table 1). This
The last step, exothermic also, corresponds to
the graduated paracyanide oxidation leading to
Mn O as final product.
3
4
Scheme 2 The paracyanide network development through oxidative degradation of coordinated N,N-dimethylbiguanide
J. Therm. Anal. Cal., 84, 2006
55

OLAR et al.
Table 1 Thermal behaviour of the complexes
The intermediates/
final product
Complex
Step
Thermal effect
Temperature interval/°C
Dmexp/%
Dmcalc/%
1
2
3
Endo
Exo
60–115
115–170
200–450
5.93
10.93
66.25
16.89
0
5.89
10.92
66.52
16.67
0
2 3 2
Mn(DMBG) (CH COO)
Mn
2
3
O(DMBG)
4 3 2
(CO )
(
(
1)
Exo
Mn
O
4
3 4
Residue (Mn O )
1
2
3
Endo
Exo
305(m. p.)*
315–360
13.59
69.22
17.19
7.34
0
13.33
69.43
17.24
7.57
0
Ni(DMBG)
2
CO
3
2)
Exo
360–730
NiO
Residue (NiO)
Residue (CuO
Residue (ZnO)
1
2
3
4
5
Endo
Endo
Exo
100–180
215(m. p.)*
230–260
2 3 2
Cu(DMBG) (CH COO)
12.38
54.81
8.71
12.19
54.25
9.25
2 3
Cu(DMBG) CO
(
3)
Exo
260–560
CuCO
3
Exo
560–800
CuO
1
2
3
4
5
Endo
Endo
Exo
100–160
220(m. p.)*
230–260
7.38
0
7.55
0
Zn(DMBG)
2
2
3 2
(CH COO)
12.22
54.29
9.14
16.97
12.16
54.08
9.22
16.98
Zn(DMBG)
CO
3
(
4)
Exo
260–560
ZnCO
ZnO
3
Exo
560–800
*
melting point
behaviour is an indicative of a smaller covalence de-
gree comparing with the other complexes of the serie.
The TG and DTG curves indicate that the first step
that occurs in the 315–360ºC range, according with
the mass loss corresponds to carbonate formation
through acetate decomposition. Next step it is an
overlap of several processes, exothermic all and diffi-
cult to separate. The residue at 400ºC display all the
characteristics of paracyanide complexes, namely a
bright black colour, the IR bands at 1505 (n(C=N)),
dicate that these molecules are involved in strong hydro-
gen interactions with the amine groups of DMBG. The
presence of such type of interactions was already evi-
denced by X-ray single crystal determinations for all hy-
drated complexes of this ligand [7, 11]. The reaction oc-
curs with a maximum rate at 165ºC. The anhydrous
compound then is melting at 215ºC. The second step,
exothermic and unitary one (according to DTG curve)
corresponds to acetate transformation into carbonate.
The IR spectrum of the intermediate isolated at 230ºC,
besides showing the characteristic bands of DMBG
shows also the new bands that could be assigned to car-
–
1
1
308 (n (CO )) and 845 cm (n (CO )). Moreover
1 3 8 3
the chemical composition corresponds to a minimal
formula Ni(CN) CO (%calc./exp., Ni, 26.46/26.38;
C, 26.90/26.94; N, 25.11/25.19). The final step corre-
–1
bonate anion at 1402 and 888 cm . The third step it is
very complex corresponding to the oxidative degrada-
tion of the N,N-dimethylbiguanide and leads to a com-
plex of the metallic ions with paracyanide having vari-
ous degree of condensation. According to the mass loss
this compound could be formulated as a complex of the
metallic carbonate with paracyanide. The IR spectrum
4
3
sponds to the transformation of the NiCO into NiO.
3
Thermal decomposition of
[Cu(C H N ) (CH COO) ]·2H O (3)
4 11 5 2 3 2 2
The thermal analysis has confirmed the compound
formulation, first step endothermic, corresponds to
water loss (Fig. 3).
–1
of this product shows an intense band at 1514 cm that
could be assigned to n(C=N) vibration mode. The bands
associated with the carbonate anion are shifted at 1382
Considering that the IR spectrum indicates clearly
–1
n ) and respectively 849 (n ) cm . This step is an over-
(
lap of at least three chemical processes and leads to
1
8
–1
the unidentate nature of acetate (nas(COO), 1624 cm ;
–1
n (COO), 1390 cm ), the water molecules are uncoordi-
s
CuCO . During the final step occurs the carbonate de-
3
nated. On this basis it is surprising that they are elimi-
nated at so high temperatures. This behaviour could in-
composition with copper(II) oxide generation at 800ºC
as final product of the thermal degradation.
56
J. Therm. Anal. Cal., 84, 2006

N,N-DIMETHYLBIGUANIDE COMPLEXES AND THEIR ANTIBACTERIAL ACTIVITY
curves. The IR spectrum of compound (4) (Fig. 4a)
revealed the unidentate nature of acetate and also the
water molecule presence. Before the thermal decom-
position it was observed the melting of complex
(
220ºC) (Table 1). The melting is followed immedi-
ately by the thermal decomposition that starts in the
first step with carbonate derivative formation as
shows the IR spectrum (Fig. 4b).
After the partial oxidative degradation of
DMBG, the carbonate paracyanide complex genera-
tion at 390ºC by oxidative condensation of DMBG
was also observed. The nature of this compound has
been confirmed by chemical analysis and IR spectra
–
1
where it appears a strong band at 1537 cm that could
be assigned to n(C=N) vibration. The bands assigned
–
1
to carbonate are present at 1392 (n ) and 810 (n ) cm
1
8
(
Fig. 4c). This step is an overlap of at least three pro-
cesses corresponding to the stepwise depoly-
merisation and oxidative degradation of the para-
cyanide, according to DTG curve. The final step cor-
Fig. 3 TG, DTG and DTA curves of
2
Cu(C (CH COO) ]·2H O
[
4
H
11
N
5
)
2
3
2
responds to the transformation of the ZnCO
ZnO, as XRD indicate.
into
3
Thermal decomposition of
Zn(C H N ) (CH COO) ]·2H O (4)
[
4
11 5 2
3
2
2
Complexes (4) and (3) have the same thermal behav-
iour and general aspect of the DTG, DTA and TG
Conclusions
A series of complexes with N,N-dimethylbiguanide
were characterised in order to obtain new effective
antibacterial agents with a large spectrum of biologi-
cal activity.
Except the Mn(II) complex, the compounds melted
before decomposition, leading to metallic oxides in
three steps. This behaviour could arise from lower lat-
tice energy and a higher degree of covalence. As it is ex-
pected, the complex with the smaller covalence degree
exhibit the highest melting point. In the case of manga-
nese(II) complex supplementary oxidation processes
that occur cover the complex melting.
The compounds display a complex thermal be-
haviour, including dehydration, acetate decomposi-
tion, paracyanide formation by oxidative degradation
of N,N-dimethylbiguanide. The intermediate prod-
ucts such are anhydrous complexes, carbonate and
some paracyanide species formed during thermolysis
were isolated and characterised. As for the carbonate
intermediates, the manganese one is the most instable
those decomposition occurring in the paracyanide
network since the other carbonate decompose after
the paracyanide network destruction.
The IR spectra for intermediates indicate the
coordinative nature of carbonate group, the manga-
nese oxidation and the paracyanide network forma-
tion in one stage of thermal decomposition.
In all cases the final products were the most sta-
ble metallic oxide as XRD indicates.
4 11 5 2 3 2 2
Fig. 4 IR spectra of a – [Zn(C H N ) (CH COO) ]·2H O and
the intermediates at b – 230ºC and c – 390ºC resulted
from thermal degradation
J. Therm. Anal. Cal., 84, 2006
57

OLAR et al.
Acknowledgements
10 B. Viossat, A. Tomas and D. Nguyen-Huy, Acta. Cryst.,
C51 (1995) 213.
1
1
1 M. Zhu, L. Lu, P. Yang and X. Jin, Acta. Cryst.,
E58 (2002) 217.
This study was financially supported by the CERES National
Romanian Research Program no. 4-128/2004.
2 M. Zhu, L. Lu, P. Yang and X. Jin, Acta. Cryst.,
C58 (2002) 272.
1
1
3 L. Lu, M. Zhu and P. Yang, Acta. Cryst., C60 (2004) 18.
4 P. Lemoine, A. Tomas, B. Viossat and
D. Nguyen-Huy, Acta. Crystallogr., C50 (1994) 1437.
5 Z. He, M. Zhu and G. Ma, Acta. Cryst., E58 (2002) 647.
6 R. Olar, M. Badea, E. Iorgulescu, N. M. Grecu, V. Lazar
and C. Balotescu, J. Inorg. Biochem., (2006) in press.
7 K. Nakamoto, (1986) Infrared and Raman Spectra of
Inorganic and Coordination Compounds, Wiley, New
York, 253–255.
References
1
2
P. Hubberstey and U. Suksangpanya, Struct. Bond.,
11 (2004) 33.
1
1
1
A. J. J. Wood, C. J. Bailey and R. C. Turner, New England
J. Med., 334 (2003) 574.
1
1
3
4
P. Pignard, Ann. Biol. Clin., 20 (1962) 325.
G. Siest, F. Roos and J. J. Gabou, Bull. Soc. Pharm.
Nancy, 58 (1963) 29.
8 J. E. Sheats, R. S. Czernuszewicz, G. C. Dismukes,
A. L. Rheingold, V. Petrouleas, J. A. Stubbe,
W. H. Armstrong, R. H. Beer and S. J. Lippard, J. Am.
Chem. Soc., 109 (1987) 1435.
5
F. Bentefrit, G. Morgant, B. Viossat, S. Leonce,
N. Guilbaud, A. Pierre, G. Atassi and D. Nguyen-Huy,
J. Inorg. Biochem., 68 (1997) 53.
6
7
8
9
R. Olar, M. Badea, E. Cristurean, V. Lazar, R. Cernat and
C. Balotescu, J. Therm. Anal. Cal., 80 (2005) 351.
P. Lemoine, M. Chiadmi, V. Bissery, A. Tomas and
B. Viossat, Acta. Cryst., C52 (1996) 1430.
M. Zhu, L. Lu, X. Jin and P. Yang, Acta. Cryst.,
C58 (2002) 158.
1
9 T. Vlase, G. Vlase, A. Chiriac and N. Doca, J. Therm.
Anal. Cal., 72 (2003) 839.
2
2
0 P. Tarte, Spectrochim. Acta, 19 (1963) 49.
1 R. Olar, M. Badea, D. Marinescu, E. Iorgulescu and
S. Stoleriu, J. Therm. Anal. Cal., 80 (2005) 363.
F. Bentefrit, A. Tomas, G. Morgan, D. Nguyen-Huy,
P. Lemoine and B. Viossat, Z. Kristallogr., 217 (2002) 1.
DOI: 10.1007/s10973-005-7177-7
58
J. Therm. Anal. Cal., 84, 2006