Research proposal related to Mixed Ligand Complexes


Research Title:  Synthesis and Characterization of Some Novel Mixed Ligand Complexes of
                          Transition Metals and Investigation of Their Biological Activities
Keywords: Mixed Ligand, Metal complexes, Biological activities
Transition metal ions are playing an important role in biological processes in the human body. For example, Ni(II), Cu(II) and Zn(II) ions are the most abundant transition metals in humans. They are found either at the active sites or as structural components of a good number of enzymes. The study of the coordination chemistry of biologically important metal ions with mixed ligands has been one of the recent developments in the field of bioinorganic chemistry. Pyridine derivatives play significant role in many biological systems as the component of several vitamins, nucleic acids, enzymes and proteins. But studies on the antimicrobial activities of their metal complexes are rare in literature.
Mixed ligand complexes differ from traditional complexes in the sense that they are having at least two different kinds of ligands with the same metal ion in a complex. The presence of more than one type of ligand in a complex increases chances of variation in properties expected for the complex.  Synthesis and characterization of mixed ligand complexes is gaining importance day by day. The increased interest in this research area has motivated many researchers to get involved in this field. 
The coordination chemistry of transition metal complexes with mixed ligands are of current interest because they can provide new materials with useful properties such as magnetic exchange, electrical conductivity , photoluminescence, non-linear optical property and antimicrobial activity.  The biological importance of mixed ligand complexes is that they are some times more effective than the free ligands. Mixed ligand complexes containing N, O and S donors are important owing to their antifungal, antibacterial and anticancer activities. It has been found that a majority of the metal complexes with 8-hydroxyquinoline possess biological activity. Its ability to get bonded with metal with its phenolic oxygen and ring nitrogen results in forming stable chelates with metals in combination with some other ligands. Amino acids are well known for their tendency to form complexes with metals having biological significance and metabolic enzymatic activities. The antibacterial and anti-fungal properties of Cu(II) complexes derived from 8-hydroxyquinoline and amino acids ( L-threonine, L-proline, L-serine and L-iolucine), have been evaluated against several pathogenic bacteria and fungi.
 Schiff bases are important in the area of research concerning to metal complex formation owing to their ease of preparation, binding ability, versatility they produce in the synthesized ligands by changing the reactants with substituted ones and various applications of the metal complexes synthesized using Schiff bases.
Biological and medicinal properties of transition metal complexes and their mechanism of action is now a modern drug discovery program.  This topic has been dominated in recent years by the use of iron complexes in the clinical trial of cancer but covers a broad field ranging from effects on bacteria viruses, etc.  Now-a-days the gold complexes are used in arthritis and nitroprusside as a vasodilator platinum based complexes also. Broad arrays of medicinal applications of metal complexes have already been widely investigated. Therefore, the pharmaceutical use of metal complexes has excellent potential.
In order to use metal complexes in practical purpose, some factors should be considered, among of them toxicity is the most important. The compounds containing sulphur are biologically highly active, but they are not free from toxicity which may play adverse effect on the corresponding system. Schiff base complexes which are reported for anticancer application are still limited to copper or iron systems. The search for novel mixed ligand metal complexes with Schiff bases with low toxicity is therefore an attractive research task to use them in the field of medicinal chemistry.
The precise nature of the Project
In this project, we are going to synthesize some novel mixed ligand transition metal complexes with 8-hydroxyquinoline (or 1,10-phenanthroline or 2,2-bipyridine) as a primary ligand and amino acids ( or dicarboxilic acids) as secondary ligands having N, O and S as donor atoms. In addition with, some new mixed ligand metal complexes with Schiff base will also be prepared.  Novel complexes which are going to synthesis in this project will be designed in such a way that they should be able to show biological activities against bacteria, fungi and certain type of tumors. The precise nature of the project will, of course, depend upon the data. 
The background information (if any) and related work already performed:
The science of coordination chemistry, an extremely attractive field in modern researches, though of comparatively recent origin is now in a state of rapid advance and has received much attention with its successful results.  Extensive researches in the field of coordination chemistry are being done and the number of published research papers and reviews in the inorganic literature are growing exponentially. This is now a central part due to an extensive and important involvement of such complexes in bio-inorganic chemistry.

Interactions between metals and medicines are becoming important subjects for study since the activities of some drugs are influenced by their interactions with metals. A number of studies have been carried out on the relationship between the effectiveness of some medicines and their coordination properties of metal ions.  Every year thousands of compounds are synthesized and many of them are subjected to pharmacological screening to determine if they have any useful bio-logical activity. But all are not equally popular due to their different efficacy, safety and toxicity to the host also.

Cisplatin is one of the most effective drugs for treating testicular, ovarian, bladder and neck cancers. Now various tumor cell lines are growing resistance to Cisplatin.  To overcome the alarming problem of microbial resistance to antibiotics, the discovery of novel active compounds against new targets is a matter of urgency. Many of the crude drugs which are sources of medicinal preparations still originate from wild-growing material. However, plant-based drugs have shortened the life span of the source of material. These problems have led the scientists to explore new and effective bioactive complexes, which may come in the modern clinical trial. Cancer is a debilitating disease that afflicts a substantial portion of the world population in all generations and is a major health problem of global concern. The numerous side effects of chemotherapeutic drugs on cancer patients including hair loss, diarrhoea, bleeding, and immunosuppression have made the process of treatment more complicated.  According to World Cancer Report from the International Agency for Research on Cancer, cases of cancer doubled globally between 1975 and 2000 will double again by 2020 and will nearly triple by 2030 (Mulcahy, 2008).  Therefore, various research initiatives are going on world-wide for the treatment of malignancy with the objective to discover some novel potent and effective antineoplastic agents, particularly those interacting with novel biological targets.  
Mixed ligand complexes with metal ion bound to two different and biochemically important ligands have aroused interest as model for metallo-enzymes. The physiologically interesting mixed ligand complexes of transition metals with amino acids play an important role in biological systems and have been a subject of great interest (Berthon et al., 1984; Shivankar et al., 2003). It is also established that mixed ligand complexes play a decisive role in the activation of enzyme and also storage and transport of active substances ( Hughes, 1987; Freeman, 1973; Aull et al., 1980). The interaction of Pd(II) and Pt(II) with salts of amino acids simply or mixed with N-based aromatic ligands to form oligonuclear complexes ( Jin et al., 2000; Hollis et al., 1989) which have been used alone or in combination with other chemotherapeutic drugs.
Schiff bases are the compounds carrying imine or azomethine (–C=N–) functional group. These are the condensation products of primary amines with carbonyl compounds. Schiff bases have gained importance in medicinal and pharmaceutical fields due to a broad spectrum of biological activities like anti-inflammatory, analgesic, antimicrobial anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. 
The nitrogen atom of azomethine may be involved in the formation of a hydrogen bond with the active centers of cell constituents and interferes in normal cell processes.
Transition metal complexes with Schiff base having nitrogen, oxygen, sulphur etc as donor atoms have already been reported to possess a wide range of biological activities against bacteria, fungi and certain type of tumors.
Schiff base and its complex derivatives, especially heterocyclic amine family, have been an important field in drug research and development due to their broad bioactivities such as antitumor, antibacterial, and antiviral activities.
Mixed ligand complexes of transition metals such as Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) using Schiff base prepared by condensing salicylaldehyde  with ethylenediamine and 8-hydroxyquinoline showed good antibacterial and antifungal activities.
The heterocyclic amine complexes with platinum and copper have been used as antitumor and antibacterial agents. The chlorinated species of 8-hydroxyquinoline has been proved as antibacterial and antifungal agents and the imido derivatives are administered to overcome zinc deficiency in animals.
Heterocyclic moieties can be found in a large number of compounds, which display biological activity.  From the above discussions, it is expected that our designed mixed ligand complexes with heterocyclic amines will be able to show biological activities and also be able to play an important in the field of medicinal chemistry.
The reason for taking up such a project including its objectives and usefulness in details
The chemistry of metal complexes is now the most active research field of Inorganic Chemistry. A survey of articles in recent issues of the journal of Inorganic Chemistry indicates that about 70% could be considered to deal with metal complexes. Progress in this area of chemistry has received an added impetus because of its many applications to chemical industry and biology. The rapidly developing field of bioinorganic chemistry is centered on the presence of metal complexes in living systems.
Mixed ligand complexes of transition elements having nitrogen, oxygen, sulphur etc as donor atoms have been used as drugs and reported to possess a wide variety of biological activities against bacteria, fungi and certain type of tumors and they have also many pharmaceutical properties. Therefore, to search new mixed ligand metal complexes with various compositions is an interesting research task.
The objectives of our proposed research are given below:
1.  To prepare a variety of novel Schiff base ligands
2. To synthesize the lighter and heavier transition metal complexes of these ligands with
    with suitable heterocyclic amines/ amino acids/ dicarboxilic acid ligands.
3. To characterize the obtained metal complexes by different physical, analytical, spectroscopic
    and X-ray crystallography data
4. To test all the ligands and the prepared complexes for antimicrobial study such as
    antibacterial,, antifungal and antioxidant properties.
5. A comparative study among themselves and as well as with standard fungicide and antibiotics
   will also be carried out.
Relevance of the project to national development/ usefulness
Our main target is to synthesise novel mixed ligand metal complexes with Schiff bases ( or heterocyclic amines/ amino acids/ dicarboxilic acids)  having O, N and S as donor atoms by using low cost effective, rapid and environmental friendly methods.
Previous and recent researches have shown a tremendous success in the use of metal complexes particularly the transition metal complexes in the treatment of cancer. In 1960 an inorganic complex cisplatin was discovered. Today more than 50 years, it is still one of the world’s bestselling anticancer drugs. Schiff base complexes of various metals like copper, gold, gallium, germanium, tin, ruthenium, irridium have already reported for their significant antitumor activity in animals.  Therefore, in this research work we have designed our ligands and complexes in such a way that the obtained products will be able to show biological activities.
 If the prepared complexes response positively to antibacterial, antioxidant and antifungal effect, it will be a great achievement for us and also for our country and this output will be able to play an important role for the socio-economic development of our country. 
Toxicity is the main problem to use metal complexes in the field of medicinal chemistry. In this research work we would like to find out the possible factors which are responsible for toxicity. It is well known that the properties of metal complexes strongly affected by the structure of ligands. So, the effect of substituents in the ligands will be investigated in details.
Methodology to be adopted in the investigation
Synthesis of Metal complexes with Schiff base
All raw materials with 99.99% purity will be purchased from Aldrich.
In order to synthesise metal complexes, we will use traditional solvent method. The first step is to synthesise Schiff base which has shown in the given flow chart. The final step involves mixing of metal salts with appropriate amount of synthesized Schiff base with another ligands.

 

Characterization:

1. FT-IR
2. NMR
3. Melting point
4. Molar Conductance
5. Magnetic moment
6. UV-vis spectra
7. Biological activity (antibacterial, antifungal, cytotoxicity and antioxidant activities)
The term-wise break up of the Project / Detailed work-plan for each term
Research Plan
Duration
Synthesis of Schiff bases and their characterization
January, 2018 to March, 2018
Synthesis of novel mixed ligand transition metal complexes with Schiff bases/ amino acids/ heterocyclic amines/ di-carboxylic acids  and their characterization
April, 2018 to August, 2018
Investigations of biological activities such as antibacterial, antifungal, cytotoxicity and antioxidant activities of prepared complexes
September, 2018 to December, 2018
January 2023
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