Structural characterization and antimicrobial activity of 1,3-bis(2-benzimidazyl)-2-thiapropane ligand and its Pd(II) and Zn(II) halide complexes

Article abstract of DOI:10.1016/j.ejmech.2005.05.006

1,3-Bis(2-benzimidazyl)-2-thiapropane(L) forms 5-coordinate square pyramidal and 4-coordinate tetrahedral, monometallic complexes with PdCl ₂ and ZnX₂ (X = Cl, Br, I), respectively. In the palladium complex, the ligand acts as a chelating tridentate, through two of the nitrogen atoms in the imidazole ring and the sulfur atom of the bridging group together with two chloride ions forming a rare five coordinate complex. In the zinc halide complexes, the ligand acts as chelating bidentate, via two of the nitrogen atoms combined with two halide ions giving common tetrahedral complexes. The ligand and its complexes are characterized by analytical data and spectroscopic methods such as FT-Raman, FT-IR (mid-IR, far-IR), ¹H and ¹³C NMR. Their antimicrobial activities are evaluated by the minimal inhibitory concentration (MIC) against 10 bacteria, each with multiple, fresh clinical isolates (10-15), and the results are compared with those of ampicillin, ciprofloxacin, cefazolin, ofloxacin, and piperacillin antibacterial agents. The compound's antifungal activities are reported on Candida albicans, Candida utilis, and Cryptococcus neoformans yeasts, each with multiple isolates (10), and the results are referenced with amphotericin-B, fluconazole and flucytosine antifungal agents. In most cases, the compounds show broad-spectrum (Gram⁺ and Gram^-) activities that are either, more active, or equipotent to, the antibiotic and antifungal agents in the comparison tests.

Full text of DOI:10.1016/j.ejmech.2005.05.006

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European Journal of Medicinal Chemistry 40 (2005) 1096–1102
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Original article
Structural characterization and antimicrobial activity
of 1,3-bis(2-benzimidazyl)-2-thiapropane ligand and its Pd(II)
and Zn(II) halide complexes
Naz M. Agh-Atabay a,*, Basaran Dulger b, Fahrettin Gucin a
a Department of Chemistry, Faculty of Arts and Science, Fatih University, 34500 Buyukcekmece, Istanbul, Turkey
b Department of Biology, Faculty of Arts and Science, Canakkale Onsekiz Mart University, Canakkale, Turkey
Received 14 July 2004; received in revised form 24 March 2005; accepted 9 May 2005
Available online 29 June 2005
Abstract
1,3-Bis(2-benzimidazyl)-2-thiapropane(L) forms 5-coordinate square pyramidal and 4-coordinate tetrahedral, monometallic complexes
with PdCl2 and ZnX2 (X = Cl, Br, I), respectively. In the palladium complex, the ligand acts as a chelating tridentate, through two of the
nitrogen atoms in the imidazole ring and the sulfur atom of the bridging group together with two chloride ions forming a rare five coordinate
complex. In the zinc halide complexes, the ligand acts as chelating bidentate, via two of the nitrogen atoms combined with two halide ions
giving common tetrahedral complexes. The ligand and its complexes are characterized by analytical data and spectroscopic methods such as
FT-Raman, FT-IR (mid-IR, far-IR), 1H and 13C NMR. Their antimicrobial activities are evaluated by the minimal inhibitory concentration
(MIC) against 10 bacteria, each with multiple, fresh clinical isolates (10–15), and the results are compared with those of ampicillin, ciprof-
loxacin, cefazolin, ofloxacin, and piperacillin antibacterial agents. The compound’s antifungal activities are reported on Candida albicans,
Candida utilis, and Cryptococcus neoformans yeasts, each with multiple isolates (10), and the results are referenced with amphotericin-B,
fluconazole and flucytosine antifungal agents. In most cases, the compounds show broad-spectrum (Gram+ and Gram–) activities that are
either, more active, or equipotent to, the antibiotic and antifungal agents in the comparison tests.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Amphotericin-B; Antifungal; Antimicrobial; Chelating; Equipotent; Fluconazole; Monometallic; Piperacillin; Pyramidal; Tridentate
1. Introduction
insecticides [4]. For instance [2-(4′-thiazolyl) benzimida-
zole], known as thiabendazole, and its several coordination
compounds aroused considerable interest in biology and medi-
cine due to their strong antimicrobial activities [5–8]. Other
bis-benzimidazole derivatives, such as 1,2-bis-(2-benzimi-
dazyl)-1,2-ethanediol, 1,3-bis(2-benzimidazyl)-2-thiapropane
and 1,5-bis(2-benzimi-dazyl)-3-thiapentane also have strong
antimicrobial characteristic against several microorganisms
[9].
Due to the following facts imidazole and benzimidazole
derivatives together with their transition metal complexes are
been extensively investigated. Their structural similarities with
the common pyrimidine and purine type nucleobases, they
attract a great deal of interest in the field of biological inves-
tigations particularly on the nucleic acid related studies. They
are the key components in a great many bioactive com-
pounds of both natural and synthetic origin. Their inhibitory
properties as regards the replication of polioviruses, adenos-
ine deaminase, and casein kinase have been demonstrated [1].
While others are important potent antiviral agents [2,3], many
are active components of biocides such as fungicides, and
In addition to their biological importance, they form stable
complexes with various transition metal ions [10–12]. The
interaction of these ions with biologically active ligands, for
instance in drugs, is a subject of great interest. Some of the
biological active compounds do act via chelation, but for most
little is known about how metal coordination influences their
activity. Although it is believed that they react selectively
towards certain biological systems [13,14]. In some cases the
* Corresponding author. Tel.: +90 212 889 0810; fax: +90 212 889 0832.
E-mail address: natabay@fatih.edu.tr (N.M. Agh-Atabay).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.05.006

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1097
Table 1
highest activity is associated with a metal atom [9,15]. The
metal oxidation state, the type and number of donor atoms,
as well as their relative disposition within the ligand are major
factors determining structural and activity relationship.
In this work, the palladium chloride and zinc halide com-
plexes with 1,3-bis(2-benzimidazyl)-2-thiapropane(L) ligand
are reported. Their antibacterial and antifungal activities are
evaluated by the minimum inhibitory concentration (MIC)
against 10 bacteria and three yeasts. Herein, we discuss the
difference of metal ion complexes as well as the free ligand
in their structural–biological activity relationship.
Some prominent IR bands of (L) and M(L)X2 complexes at 3350–170 cm−1
region
Ligand (L) 1930, 1890, 1772 m(ar. patterns), 1625 m(C=C),
1590 mas(C=N), 1440 ma(C=N), 1273 m(C−N), 735 d(C=Car),
506, 477, 438, 361, 307, 270, 218
Zn(L)Cl2
3325 m(N−H), 1949, 1910, 1791 m(ar. patterns),
1623 m(C=C), 1596 mas(C=N), 1452 ms(C=N), 1155 m(C−N),
748 d(C=Car), 432 d(C=Har), 514, 486 m(Zn–N), 438, 363,
320-248 (v. br.) mas(Zn–Cl), 197 ms(Zn–Cl)
Zn(L)Br2
Zn(L)I2
3325 m(N−H), 1623 m(C=C), 1595 mas(C=N), 1451 ms(C=N),
1279 m(C−N), 748 d(C=Car); 512, 487 mas(Zn–N),
438 d(C=Har), 253 mas(Zn–Br), 198 ms(Zn–Br)
3329 m(N−H), 1623 m(C=C), 1595 mas(C=N), 1448 ms(C=N),
1278 m(C−N), 750 d(C=Car), 512, 487 mas(Zn–N), 437
d(C=Har), 359, 303, 288, 250 ms(Zn–N), 209, 201,
183mas(Zn–I)
2. Chemistry
Ligand (L) is prepared by literature procedures [9,16]. Syn-
theses of the palladium and zinc halide complexes are carried
under reflux in absolute ethanol. Full general procedures for
preparation of these compounds are given in the experimen-
tal and the reactions sequence are shown in Figs. 1 and 2. The
spectroscopic data from FT-IR, FT-Raman, 1H and 13C NMR,
do provide useful information for their formation and struc-
tural characterization. These data and their assignments are
reported in Tables 1–4. Optimized structures of ligand and
complexes are presented in Figs. 3–5. Required analytical data
and physical properties are summarized in the end of each
experimental.
Table 2
Prominent Raman bands of (L), metal halides and complexes at 3350–
100 cm−1 region (solid)
ZnCl2 m(228), ZnBr2 m(164), ZnI2 m(121) and PdCl2 m(279)
Ligand (L) 3070, 3060 m(C−Har), 2975 m(C−H), 2932 m(C−H),
1626 m(C=N), 1595 m(C=Car), 740 d(C=Car), 578, 516, 439,
360, 308, 279, 151
Zn(L)Cl2
Zn(L)Br2
Zn(L)I2
3082 m(C−Har), 2942, 2926, 2894 m(CH2), 1600 m(C=C),
1537 m(C=N), 1450 m(C=N), 1280 m(C−N), 744 d(C=Car),
488 mas(Zn−N), 252 ms(Zn−N), 251 mas(Zn−Cl),
196 ms(Zn−Cl)
3074, 3063 m(C−Har), 2968, 2942, 2927 m(CH2), 1621
m(C=C), 1595 mas(C=N), 1529, 1451 m(C=N), 1281, 1252
m(C−N), 760 d(C=Car), 488 mas(Zn−N), 365, 288, 251,
ms(Zn−N), 251 ms(Zn−N), 180 mas(Zn−Br), 143 ms(Zn−Br)
3067 m(C−Har), 2969, 2944 m(CH2), 1622 m(C=N), 1595
mas(C=C), 1448 m(C=N), 1278 m(C−N), 750 d(C=Car), 488
mas(Zn−N), 251ms(Zn−N), 251 ms(Zn−N), 180 mas(Zn−I),
143 ms(Zn−I)
3. Theoretical calculation
Optimizing a molecule involves finding the most stable
geometry, or minimum energy structure, of a chemical sample.
CACHE work system pro version 5.02 package program uses
three different methods for geometry optimization of a mol-
ecule: Optimizing with mechanics, MOPAC or DGauss. The
most widely used of these methods are the MOPAC and
DDauss calculations methods. MOPAC parameters are
obtained by fitting experimental heats of formation, geom-
etries, permanent dipoles, and ionization potentials, whereas
DGauss uses density functional theory (DFT) methods. DFT
models provide an approximate solution to the Schrödinger
equation using only mathematical approximations. There are
many different sets of calculation for each of these methods.
We have examined several of these methods, such as on
MOPAC (AM1, MP3, MP5, MNDOd), and on DGauss (B88-
PW91, B88-LYP and D-VWN all using DFT methods). We
found that the B88-PW91 set gives the most stable structure
for both the ligand and the complex.
4. Pharmacology
Fresh clinical isolates are obtained from Faculty of Medi-
cine, University of Uludag (Turkey), and are supplemented
by stock cultures of fresh clinical isolates of several species
to achieve target numbers. The total numbers of isolates are
Fig. 1. Syntheses of ligand (L) + 2HCl, refluxed in 5 M HCl for 24 h.
Fig. 2. Syntheses of ligand (L) neutralized with dilute base.

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N.M. Agh-Atabay et al. / European Journal of Medicinal Chemistry 40 (2005) 1096–1102
Table 3
1H NMR spectra data of (L) and M(L)X2 complexes (DMSO-d6)
Ligand (L) dH 3.85 (4H, s, CH2), 6.96 (4H, s, H5 and H6),
7.32 (4H, s, H4 and H7), (2H, NH not detected)
Zn(L)Cl2
Zn(L)Br2
Zn(L)I2
dH 4.06 (4H, s, CH2), 7.39 (4H, s, H5 and H6),
7.68 (2H, s, H7), 8.29 (2H, s, H4), 13.68 (2H, s, NH)
dH 4.02 (4H, s, CH2), 7.40 (4H, s, H5 and H6),
7.70 (2H, s, H7), 8.28 (2H, s, H4), 13.68 (2H, s, NH)
dH 4.10 (4H, s, CH2), 7.3.95 (4H, s, H5 and H6),
7.83 (4H, s, H4 and H7), 13.80 (2H, br, NH)
dH 4.56 (2H, d, JHgg’ = 15.20 Hz), 5.55 (2H, d,
JHg’g = 15.20 Hz), 7.2–7.6 (6H, m, H5, H6 and H7),
8.60 (2H, d, H4 : J = 8.00), 13.38 (2H, s, NH)
Pd(L)Cl2
Fig. 4. Optimized structure of Zn(L)X2 complex.
Table 4
13C{1H} NMR (125 MHz) spectra data of (L) and M(L)X2 complexes
(DMSO-d6)
Ligand (L) dC 29.04 (2C, CH2), 115.17 (4C, C4 and C7), 122.19 (4C,
C5 and C6), 138.93 (4C, C8 and C9), 152.10 (2C, C2)
Zn(L)Cl2
Zn(L)Br2
Zn(L)I2
dC 25.17 (2C, CH2), 112.25 (2C, C7), 118.05 (2C, C4),
123.85 (2C, C6), 124.25 (2C, C5), 132.36 (2C, C8), 139.10,
(2C, C9), 151.95 (2C, C2)
dC 25.11 (2C, CH2), 112.30 (2C, C7), 118.10 (2C, C4), d
123.65 (2C, C6), 124.15 (2C, C5), 132.85 (2C, C8), 139.0,
(2C, C9), 151.80 (2C, C2)
25.10 (2C, CH2), 12.45 (2C, C7), 118.25 (2C, C4), 123.75
(2C, C6), 124.18 (2C, C5), 132.93 (2C, C8), 139.20, (2C,
C9), 151.78 (2C, C2)
Fig. 5. Optimized structure of Pd(L)Cl2 complex.
Pd(L)Cl2
dC 32.17 (2C, CH2), 112.83 (2C, C7), 118.35 (2C, C4),
123.72 (2C, C6), 124.44 (2C, C5), 132.66 (2C, C8), 139.98,
(2C, C9), 153.92 (2C, C2)
together with NAD from Sigma Chemicals. Amphotericin-B
(antifungal and antiprotozoal commonly used for treatment
of mycotic infection, including cryptococcosis, histoplasmo-
sis, blastomycosis, candida, and also used medication for HIV
and AIDS patients), fluconazole (an azole antifungal agent
for treatment of oral thrush and vaginal infections), and flucy-
tosine (for treatment of susceptible fungal infections, such as
Cryptococcus) are obtained from Fluka. Mueller Hinton
media, nutrient broth and malt extract broth are purchased
from Difco and yeast extracts is obtained from Oxoid.
5. Results and discussion
5.1. Chemistry
Fig. 3. Optimized structure of ligand (L).
5.1.1. Infrared and Raman spectra
The N–H stretching of imine group, which is not detected
in the free ligand due to the fluxional behavior of the imine
hydrogen atoms, appears in all four complexes as a medium
broad band at ca. 3325 cm−1. This supports the contention
that coordination most probably occurs through both bis-
3 and 3′ nitrogen atoms, causing inhibition of the fluxional
behavior of imine hydrogen atoms.
The characteristic m(CH) modes of ring residues and eth-
ylenic group are observed as expected in the 3100–2850 cm−1
spectral regions in both IR and Raman for the ligand and the
complexes. Specific differences between spectra in this region
show strong support for the formation of new complexes
(Tables 1 and 2). Slight down field shift of mas(C=N) vibra-
tions, and appearance of strong bands at ca. 1500 cm–1 for
115 bacteria and 30 fungi, representing 10 and three species,
respectively (Tables 5 and 6).
Standardized powder samples of ampicillin (amino-
penicillin, broad-spectrum antibiotic for treatment of Gram-
negative and Gram-positive bacteria), ciprofloxacin (Cipro is
considered the “gold standard” therapy for many types of
Gram-negative infections, including Pseudomonas aerugi-
nosa, and has approved for the inhaled form of anthrax), cefa-
zolin (a semisynthetic cephalosporin antibiotic for intramus-
cular or intravenous administration), floxacin (broad activity
anti-infective drug used for the treatment of lower respira-
tory infections and with inhibition of DNA-gyrase activity),
piperacillin (b-lactamase a sensitive antibiotic effective on
Gram-negative and Gram-positive bacteria), are purchased

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Table 5
Antibacterial activities of the ligand (L) and complexes, evaluated by MIC for 10 bacteria and their rate of susceptibility to five compared antibiotics
M
N
MIC (µg ml−1 a
)
% isolates MICs < 64 µg ml−1
% isolates suspectibleb
AM CI CF OF PI
(L)
Zn(L)Cl2
Zn(L)Br2
Zn(L)I2
Pd(L)Cl2
50% 90% Range
50% 90% Range
50% 90% Range
50% 90% Range
50% 90% Range
1
2
3
4
5
A
B
C
D
E
F
G
H
I
15
15
15
10
10
10
10
10
10
10
32
16
16
8
64
32
16
16
16
32
64
32–128
16–32
16–32
8–32
32
16
8
32
16
16
8
32–128
8–16
8–16
4–8
32
8
64
16
32
8
32–128
8–16
8–32
4–8
32
8
128 32–128
8
16
16
32
8
8–32
8–16
8–32
4–8
85
90
96
88
94
7
60
70
93
6
50
60
16
16
8
8–16
8–16
4–8
8
100 100 100 100 100 67
100 100 100 100 100
100 100 100 100 100 12
100 100 100 100 100 100 80
100 100 100 100 100 16 100
97
100 67
100 88
100 88
8
8
8
0
100
4
8
4
8
100 96
16
16
32
16–32
16–32
32–128
8
8
4–8
8
16
16
8–16
8–16
8
16
16
64
8–16
8–16
32–128
8
16
16
16
8–16
4–16
16–32
0
4
80
92
100
8
16
64
8–16
32–128
8
8
8
96
32
32
128 32–128
32
16
92
0
97
0
96
0
96
0
94
0
100 100 100 97
100
100
100
100
> 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256
> 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256
> 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256 > 256 > 256 256–> 256
100 96
100 96
100 87
85
85
0
92
94
83
0
0
0
0
0
J
0
0
0
0
0
M: microorganimsms; N: number of isolates. (A) S. aureus, (B) E. coli, (C) E. aerogenes, (D) K. pneumoniae, (E) A. faecalis, (F) C. freundii, (G) S. pyogenes, (H) P. vulgaris, (I) P. mirabilis, (J) E. faecalis.
1 = Ligand (L), 2 = Zn(L)Cl2, 3 = Zn(L)Br2, 4 = Zn(L)I2, 5 = Pd(L)Cl2.
a 50% and 90%, MICs at which 50 and 90% of the isolates are inhibited, respectively.
b Susceptibility breakpoints are in parentheses with µg ml−1 values. AM, ampicillin (< 8.0); CI, ciprofloxacin (< 1.0); CF, cefazolin (< 8.0); OF, ofloxacin (< 2.0); PI, piperacillin (< 16).
Table 6
Antifungal activities of the ligand (L) and complexes, evaluated by MIC for three yeasts and their rate of susceptibility to five compared antifungal
M
N
MIC (µg ml−1 a
)
% isolate, MICs < 64 µg ml−1
% isolate sus.b
FLU FL
(L)
90%
8
Zn(L)Cl2
Zn(L)Br2
Zn(L)I2
Pd(L)Cl2
50%
Range 50%
90%
Range 50%
90%
Range 50%
90%
Range 50%
≤ 0.125–44
≤ 0.125–44
90%
Range
4–8
1
2
3
4
5
AM
100
100
98
A
B
C
10
10
10
8
8
8
8–16
2–8
4
4
4
8
8
8
4–8
4–8
4–8
4
4
4
8
8
8
4–8
4–8
4–8
2
2
4
4
4
8
8
8
8
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
92
8
4–8
8
8–16
4–8
4
4–8
M: microorganisms; N: number of isolates. (A) C. albicans, (B) C. utilis, (C) C. neoformans. 1 = Ligand (L), 2 = Zn(L)Cl2, 3 = Zn(L)Br2, 4 = Zn(L)I2, 5 = Pd(L)Cl2.
a 50% and 90%, MICs at which 50% and 90% of the isolates are inhibited, respectively.
b Susceptibility breakpoints are in parentheses with µg ml−1 values. AM, amphotericin-B (< 16); FLU, fluconazole (< 8.0); FL, flucytosine (< 16.0).