Spectral, thermal and kinetic studies of charge-transfer complexes formed between the highly effective antibiotic drug metronidazole and two types of acceptors: σ- And π-acceptors

Article abstract of DOI:10.1016/j.saa.2015.01.029

Understanding the interaction between drugs and small inorganic or organic molecules is critical in being able to interpret the drug-receptor interactions and acting mechanism of these drugs. A combined solution and solid state study was performed to describe the complexation chemistry of drug metronidazole (MZ) which has a broad-spectrum antibacterial activity with two types of acceptors. The acceptors include, σ-acceptor (i.e., iodine) and π-acceptors (i.e., dichlorodicyanobenzoquinone (DDQ), chloranil (CHL) and picric acid (PA)). The molecular structure, spectroscopic characteristics, the binding modes as well as the thermal stability were deduced from IR, UV-vis, ¹H NMR and thermal studies. The binding ratio of complexation (MZ: acceptor) was determined to be 1:2 for the iodine acceptor and 1:1 for the DDQ, CHL or PA acceptor, according to the CHN elemental analyses and spectrophotometric titrations. It has been found that the complexation with CHL and PA acceptors increases the values of enthalpy and entropy, while the complexation with DDQ and iodine acceptors decreases the values of these parameters compared with the free MZ donor.

Full text of DOI:10.1016/j.saa.2015.01.029

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Accepted Manuscript
Spectral, thermal and kinetic studies of charge-transfer complexes formed be-
tween the highly effective antibiotic drug metronidazole and two types of
acceptors: σ- and π-acceptors
Moamen S. Refat, Hosam A. Saad, Abdel Majid A. Adam
PII:
S1386-1425(15)00039-6
http://dx.doi.org/10.1016/j.saa.2015.01.029
SAA 13197
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomo-
lecular Spectroscopy
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 November 2014
8 January 2015
15 January 2015
Please cite this article as: M.S. Refat, H.A. Saad, A.M.A. Adam, Spectral, thermal and kinetic studies of charge-
transfer complexes formed between the highly effective antibiotic drug metronidazole and two types of acceptors:
σ- and π-acceptors, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2015), doi: http://
dx.doi.org/10.1016/j.saa.2015.01.029
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Spectral, thermal and kinetic studies of charge-transfer complexes formed
between the highly effective antibiotic drug metronidazole and two types of
acceptors: - and -acceptors
Moamen S. Refata,b,*, Hosam A. Saada,c and Abdel Majid A. Adama
a
Department of Chemistry, Faculty of Science, Taif University, Al-Haweiah, P.O.
Box 888, Zip Code 21974, Taif, Saudi Arabia
b Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt
c Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
Abstract
Understanding the interaction between drugs and small inorganic or organic
molecules is critical in being able to interpret the drug-receptor interactions and acting
mechanism of these drugs. A combined solution and solid state study was performed
to describe the complexation chemistry of drug metronidazole (MZ) which has a
broad-spectrum antibacterial activity with two types of acceptors. The acceptors
include, -acceptor (i.e., iodine) and -acceptors (i.e., dichlorodicyanobenzoquinone
(DDQ), chloranil (CHL) and picric acid (PA)). The molecular structure, spectroscopic
characteristics, the binding modes as well as the thermal stability were deduced from
1
IR, UV-vis, H NMR and thermal studies. The binding ratio of complexation (MZ:
acceptor) was determined to be 1:2 for the iodine acceptor and 1:1 for the DDQ, CHL
or PA acceptor, according to the CHN elemental analyses and spectrophotometric
titrations. It has been found that the complexation with CHL and PA acceptors
increases the values of enthalpy and entropy, while the complexation with DDQ and
iodine acceptors decreases the values of these parameters compared with the free MZ
donor.
Keywords: Metronidazole, Charge-transfer complex, -acceptor, -acceptor, TG and
DTG.
_________
* Corresponding author.
E-mail address: msrefat@yahoo.com (M.S. Refat).
Tel.: 00966551352497
1

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1. Introduction
The study of the charge-transfer (CT) or proton-transfer interaction of drugs
and small molecularly acceptors have been a great deal of interest. It is a relevant
topic in life science, pharmacology, chemistry, and medicine. During the last decade,
a large number of studies have been reported on drug-acceptor interaction in solid
state and in solution. The drug-acceptor complexation is an important technique that
is cheaper, simpler, and more efficient than the methods of drug determination
described in the literature. Also, the study of this complexation may be useful in
understanding the drug-receptor interactions and the mechanism of drug action.
Furthermore, the crystalline drug-acceptor complexes have a vital role in biological
systems such as antimicrobial activity and DNA-binding. Literature shows that these
complexes exhibit potential antimicrobial properties against some Gram-positive and
Gram-negative bacteria as well as fungi [1-10]. Nitroimidazole derivatives have
showed broad varieties of biological activities especially antimicrobial activity. 5-
nitroimidazole based drugs have been applied to treat the infections induced by
bacteria and a range of pathogenic protozoan parasites for many years because
nitroimidazole derivatives can undergo bioreduction to produce electrophilic
substances that can damage portion and nucleic acids [11]. In this work, the drug-
acceptor interaction between drug metronidazole (MZ) and some - and -acceptors
was reported. The acceptors include, -acceptor (i.e., iodine) and -acceptors (i.e.,
dichlorodicyanobenzoquinone (DDQ), chloranil (CHL) and picric acid (PA)).
Metronidazole (MZ; C6H9N3O3) chemically 1-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole, the structure of which is shown in Scheme 1, is a 5-nitroimidazole-
based drug with highly antibiotic and anticoccidial activity [12]. It is an antibiotic
used to treat different kinds of infections and frequently used in treating anaerobic and
protozoal infections [13-15]. MZ is used in surgery, especially breast cancer and
colon cancer surgery [16], and as a promoter to induce the growth of cattle, pigs, and
poultry and improve feed efficiency [17]. It is generally well tolerated, although it has
been banned by many countries and areas from use in food producing animals
because MZ is now believed to possess genotoxic, carcinogenic and mutagenic side
effects. MZ binds to DNA causing its damage; on the other hand it is capable of
inducing gene mutations in mammalian cells. It may be carcinogenic in mice and rates
if used in large doses for an extended period of time [18-20]. The objectives of the
current study were as follows: (i) to synthesize the CT complexes of drug MZ with
iodine, DDQ, CHL and PA acceptors; (ii) to characterize the formed complexes
structurally via infrared (IR), 1H NMR, and electronic absorption spectroscopy; (iii) to
observe and differentiate the thermal behavior of the reported complexes using TG
and DTG techniques.
OH
N
N
NO2
Scheme 1. Chemical structure of drug metronidazole (MZ).
2

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2. Experimental methodologies
2.1 Reagents and solutions
Drug metronidazole (MZ; C6H9N3O3; 171.15) was obtained from Sigma-
Aldrich Chemical Company (USA) with a stated purity of greater than 98% and it was
used as such without further purification. The electron acceptors iodine (I2; 253.8),
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; C8Cl2N2O2; 227), chloranil (CHL;
C6Cl4O2; 245.88) or picric acid (PA; C6H3N3O7; 229.10) (Scheme 2) and other
spectroscopic grade solvents were purchased from Aldrich and Merck Chemical
Companies and were used without modification. All chemicals used in this study were
of analytical reagent grade and used without further purification. A standard stock
solutions of MZ and each acceptor at a concentration of 5.010-3 M were freshly
prepared prior to each series of measurements by dissolving precisely weighed
quantities in a 100 mL volumetric flask using methanol or chloroform solvent. The
stock solutions of MZ and acceptors were protected from light. Solutions for
spectroscopic measurements were made by mixing appropriate volumes of donor and
acceptor stock solutions with the solvent immediately before running the spectra.
2.2 Reaction chemistry
To obtain the CT complexes, a methanol or chloroform solution of MZ (1
mmol) was stirred with a solution of each acceptor (1 mmol) in the same solvent for
ca. 30 min on a magnetic stirrer at room temperature. A change in color developed,
and the volume of the solution was reduced to one-half by evaporation on a water
bath, resulting in the precipitation of the solid CT complexes. The formed complexes
were isolated, filtered off and washed twice thoroughly with the minimum given
solvent to obtain the pure products. The solid products were then collected and dried
in vacuo for 48 h. Strong change in colors was observed upon mixing solutions of the
MZ donor with any of the acceptors. These observed new colors are dark brown for
MZI2 and MZCHL, dark-reddish brown for MZDDQ and dark yellow for
MZPA reaction mixtures. These changes in colors represent strong evidence of the
CT interactions between the donor and each of the acceptors. These complexes were
1
characterized by spectroscopy (IR, H NMR and UV-vis) elemental and thermal
analysis.
O
OH
O
Cl
Cl
CN
CN
O2N
NO2
Cl
Cl
Cl
Cl
O
NO2
PA
O
DDQ
CHL
Scheme 2. Chemical structure of the DDQ, CHL and PA acceptors.
3