Copper-Drug Based Complexes: Antimicrobial, Antioxidant and Pharmacological Study
Ouiza Hamrani1, Sultana Boutamine1, Safia Kellou-Tairi2 and Zakia Hank1*
1Université des Sciences et de la Technologie Houari Boumediene, Laboratoire d’Electrochimie-Corrosion, Algérie.
2Université des Sciences et de la Technologie Houari Boumediene, Laboratoire de Physico-Chimie Théorique et de Chimie Informatique, Algérie.
Submission: October 29, 2017; Published: November 30, 2017
*Corresponding author: Zakia Hank, Université des Sciences et de la Technologie Houari Boumediene, Laboratoire d’Electrochimie-Corrosion, Métallurgie et Chimie Minérale, Faculté de Chimie, Algérie ; Tel: 00213550627595; Email: firstname.lastname@example.org
How to cite this article: Ardhendu K M. Silver Nanoparticles as Drug Delivery Vehicle against Infections. Glob J Nano. 2017; 3(2): 555610. DOI:10.19080/GJN.2017.03.555610
The study on complexation of drug molecules with various metal ions is an important field of research in the chemical, biochemical, medicinal and pharmacological point of views . Our body possesses a large number of metal ions for operating normal physiological activities and we also intake a number of metals as drug, dietary factor, drinks and we also come in close contact with different drugs. It’s also well established that many pathological situations involve deregulation in the metabolism of metals: therapeutic responses are then necessary and although most drugs or compounds used in medicine are purely organic. The challenge is to enhance the properties of these drugs by complexing them and to study their interaction with the trace elements present in the human organism. In fact, the complexation offers the metal ion a multitude of coordination possibilities and a wide range of geometries. As a result, the metal complexes, due to their thermodynamic and kinetic properties, and in some cases their redox activities, offer novel mechanisms of action that organic compounds do not exhibit themselves so it’s very important to control all these properties to obtain the desired therapeutic effect when a drug or a metal complex is introduced into the body or the cell [2-4].
The interest of this study is to examine the modifications that the metal can make to the properties of an organic molecule when the latter is coordinated to it. Copper complexes have attracted great deal of attention due to their therapeutic applications as antimicrobial and antioxidant so, we have been interested in the study of the complexation of this metal by some drug molecules such as Paracetamol, Indomethacin and Spiramycin. Few works report similar study [5-9].
The results of our investigations (Table 1) show that some metal complexes are more toxic than their parent ligands against
the same microorganism and under identical experimental conditions. This would suggest that chelation could facilitate the ability of the complex to cross a cell membrane. It’s well established that the mode of action of antimicrobials may involve various targets in the microorganisms . These targets include the following: the higher activity of the metal complexes may be due to the different properties of the metal ions upon complexation . According to Overtone’s concept  of cell permeability, the lipid membrane that surrounds the cell favors the passage of only lipid-soluble materials, so lipophilicity is an important factor controlling the antifungal activity. On the other hand and upon Tweedy’s chelation theory  the polarity of the metal ion will be reduced because of the partial sharing of the positive charge of the metal with the donor groups present in the ligand. Thus, chelation enhances the penetration of the complexes into lipid membranes. These results are corroborated by DFT calculations.
The comparison of the LD50 values of the complexes with
that of the free ligands shows formally that the complexes are
less toxic with a much higher tolerance to the synthetic product.
Some results of this investigation are given in Table 2.
As a result, we find that batches treated with CuP complex
with doses lesser than 50% of determined lethal dose do not
affect the weight evolution of the mice. Therefore, the results
obtained suggest that CuP complex is fairly non-toxic (Table 3).
The injection of Carrageenan induces the liberation of
bradykinin, which later induces the biosynthesis of prostaglandin
and other autacoids, which are responsible for the formation of
the inflammatory exudates [14-16]. The study of the acute antiinflammatory
tests showed that copper complexes produced a
significant (P=0.028) reduction at 6h in Carrageenan induced paw
edema when compared to the positive control group (Diclofenac
at 50mg/Kg-body weight). Some results are gathered in Figure
1. These results suggest that the complexation of indomethacin
increases its anti-inflammatory effect and that of paracetamol
confers anti-inflammatory activity.
The antioxidant activity of Cu(II) complexes was measured
in terms of their hydrogen donating or radical scavenging ability
by UV–vis spectrophotometer using the stable 2,2-diphenyl-
1-picrylhydrazyl radical (DPPH) (DPPH: 18H12N5O6). For
illustrating this study, we give here the results corresponding
to CuP tests. Radical scavenging activity of paracetamol and
CuP complex as well as the standard was increased in a dosedependent
manner; nevertheless, paracetamol and CuP complex
showed less good activities as a radical scavenger compared to
that of ascorbic acid, which was used as a standard. However,
they exhibit appreciable activity with 80% in percentage
scavenging in from a concentration of 300μg/mL.
The electronic structures of the studied compounds have
been investigated by the quantum chemical parameters like
energy of the highest occupied molecular orbital (EHOMO), energy
of the lowest unoccupied molecular orbital (ELUMO), LUMOHOMO
energy gap (ΔE) and natural atomic charges calculated
by natural population analysis. The HOMO and the LUMO are
important parameters in organ metallic chemistry especially in
chemical reactivity. ΔE is an important stability index helping to
characterize the chemical reactivity and kinetic stability of the
In the copper complexes, the EHOMO and ELUMO are negative
(Table 4) which indicates their stability. The complexes have
the smallest energy gap (beta), so they are more reactive
than the parent ligands since they easily offer electrons to an
Microbial studies suggested that the copper complexes
showed importantly raised antibacterial and antifungal
activities and presented higher antimicrobial activity than the
corresponding free ligand.
Based on the results of the toxicological study, the acute
toxicity of the complexes tested on mice of NMRI strain revealed
that the copper - drug complex is generally not toxic. The antiinflammatory
assay study shows that the copper-ligand binding
induced an anti-inflammatory effect to the drug molecule, which thus changes the therapeutic class. These experimental tests are
corroborated by the DFT study which shows the higher reactivity
of the complex with respect to the free ligand.
The authors would like to extend their grateful thanks
to F. Benguergoura, A. Mokrani, K. Tahar Djebbar (Institut
Pasteur de Dely Ibrahim, Alger-Algérie), A. Benabdelouahid
(Département de Pharmacie, Université d’Alger-Algérie) and
Dr. H. Henni (Laboratoire Nationale de Contrôle des Produits
Pharmaceutiques, Alger-Algérie) for technical support.