SYNTHESIS AND CHARACTERIZATION OF METRONIDAZOLE (FLAGYL) DRUG – METAL COMPLEXES OF NICKEL (II), MANGANESE (II), COPPER (II) AND IRON (II) IONS
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TABLE OF CONTENTS
TITLE PAGE i
CERTIFICATION ii
DEDICATION iii
ACKNOWLEDGEMENT iv
TABLE OF CONTENT v
ABSTRACT vii
1.0 CHAPTER ONE
1.1 Introduction 1
1.2 Antibiotic : Classification and side effect. 2
1.2.1 Classification of Antibiotics 2
1.2.2 Side effect of Antibiotic 3
1.3 Flagyl (Metronidazole) 4
1.3.1 Mechanism of action 4
1.3.2 Resistance 5
1.3.3 Spectrum Activity of metronidazole. 5
1.3.4 Pharmacokinetic of Metronidazole 6
1.3.5 Toxicity of Metronidazole 6
1.3.6 Half-life of Metronidazole 7
1.3.7 Topical Administering of Metronidazole 7
1.4 Metal Complexes 8
1.5 Properties of Ligands 8
1.6 Properties of Nickel, Biological importance and Toxicity. 9
1.7 Properties of Iron, Biological importance and Toxicity 10
1.8 Properties of Cobalt, Biological importance and Toxicity 10
1.9 Properties of Manganese, Biological importance and Toxicity 11
1.10 Aim of the project 12
2.0 CHAPTER TWO
2.0 Apparatus, reagents and experiments 13
2.1 Flagyl Fe(ii) complex formation 15
2.3 Flagyl Co(ii) complex formation 15
2.3 Flagyl Ni(ii) complex formation 16
2.4 Flagyl Mn(ii) complex formation 16
2.5 Characterization 17
2.6 Melting point determination 17
2.7 Atomic Absorption Spectra 18
3.0 CHAPTER THREE
3.1 Result of flagyl Fe(ii) complex formation 19
3.2 Result of flagyl Co(ii) complex formation 19
3.3 Result of flagyl Mn(ii) complex formation 19
3.4 Result of flagyl Ni(ii) complex formation 19
3.5 Result of solubility test 20
3.6 Result of melting point determination 20
3.7 Result of Atomic Absorption Spectra (AAS) 21
4.0 CHAPTER FOUR
4.1 Conclusion and Recommendation 22
4.2 References 23
ABSTRACT
Metronidazole (flagyl) metal complexes were prepared from the reactions of metronidazole (flagyl) and FeS04.7H20, NiCO3.7H2O, MnSO4.7H2O and CoSO4.H2O. The complexes were characterized using physical properties such as melting point determination; solubility and Atomic Absorption spectra (AAS), the result obtained from each property showed that the drug metal complexes were more effective and powerful than the parent drug.
CHAPTER ONE
1.l INTRODUCTION
Antibiotics belong to a class of compounds of biosynthetic or semi-synthetic in nature. Most of them are produced by various species of microorganisms and other living synthetic and are capable in small concentrations of inhibiting the growth of or killing bacteria and other micro-organisms. An extensive review on the metal complexes of various antibiotics was published (1) It includes complexes of tetracycline and bleomycin, valinomycin, beauverian and otherenniatins, gramicidins, nactins, lasalcid, monensin, calcimycinand related antibiotics D-eycloserine and related aminoacids with antibiotics properties and iron-containing antibiotics.
Chlorotetracycline (aureomucin) and oxytetracycline (terramycin) were shown to have high affinity for the cations of heavy metals, the acidity of terracycline towards first row transition metals ions and the corresponding stability constants of the metal complexes have been reported. The stoichiometeries and concentrations of the different metal complexes formed by tetracyclines in vivo could be assessed on a quantitative basis by using high speed.(2) Thiadiazole derivates have been reported to be biologically versatile compounds, possessing antiviral, anti-bacterial, anti-pyretic, antifungicidal and analgesic activities. Complexes of 4-acetyl-2-(ace- tylamino)-5-dimethyl- 2-l, 3, 4-thiadiazole with cadmium, mercury and first row transition metals have been described.
1.2 ANTIBIOTICS -.CLASSIFICATION AND SIDE EFFECT
An antibiotics are drugs that kills or slow down the growth of bacterial, antibiotics are one class of antimicrobials, a large group which also include anti-viral, anti-fungal and anti-parasitic drug. Antibiotics are chemicals produced by or derived from microorganism (i.e bugs, germs such as bacteria and fungi), the first antibiotics was discovered by Alexander Fleming in 1928 in significant breakthrough for medical science.(3)
Antibiotics are among the most frequently prescribed medications in modern medicine , some antibiotics are bactericidal meaning that they work by killing bacteria ,other antibiotics are bacteriostatic meaning that they work by stopping bacteria multiplying each different type of antibiotics affect different bacteria in different ways for example an antibiotics might inhibit a bacterium ability to turn glucose into energy or it ability to construct its cell wall when this happens the bacterium dies instead of reproducing.
1.2.1 Classification of Antibiotics
Amino glycoside antibiotics are used to treat infections caused by gram- negative, it may be use with penicillin or cephalosporin which give much prolonged attack on the bacteria, (5) amino glycoside work quite well but bacteria can become resistant to them since amino glycoside are broken down easily into the stomach and they can’t be given by mouth but must be injected.
Cephalosporin are grouped into generations by their antimicrobial properties, cephalosporin are categorized chronically and are therefore divided into first, second and third generations currently three generations of cephalosporin are recognized and fourth has been proposed .Each newer has greater gram negative antimicrobial properties than the proceeding generation. The latter generation cephalosporin have greater effect against resistant bacteria which has been used to treat pneumonia, strep throat, staph infection, tonsillitis, bronchitis,otitis media, various types of skin infection, gonorrhea. Cephalosporin antibiotics are commonly used for surgical prophylaxis,which is closely related to penicillin. Penicillin was first antibiotics discovered by Alexander Fleming in 1929, penicillin are used to treat skin infections, dental infection, ear infection, respiratory tract infection, urinary tract infection, gonorrhea.They are sometimes combined with other ingredients called beta lactamase inhibitory, which protect the penicillin from bacterial enzymes that may destroy it before it can do it work, are usually very safe,it has an allergic reaction which can be severe, people who have been allergic to Cephalosporin are likely to be allergic to penicillin the most commonly prescribed penicillin are Amoxillin, Ampicillin, Becampicillin, Becampicillin, Becampicillin, oxacillin(7).
1.2.2 Side Effect of Antibiotics
Antibiotic can literally save lives and are effective in reacting illness caused by bacteria infections, however like all drugs they have potential to cause unwanted side effect, many of these side effect are not dangerous though they can make life miserable while the drug is been taken. In general, antibiotics rarely cause serious side effects, The most common side effect from antibiotics are diarrhea, nausea, vomiting, fungal infection of the mouth digestive tract and virginal can also occur because antibiotics destroys the protective good bacterial in the body (which prevent growth of any other organism)and also the bad ones which responsible for the infection being treated. Some people are allergic to antibiotics particularly penicillin, allergic reactions which cause swelling of the face, itching, skin rashes and severe cases like difficulties in breathing.
1.3 FLAGYL (METRONIDAZOLE)
Metronidazole is one of the main stay drugs for the treatment of anaerobic infections and is the treatment choice for most patients with mild to moderate Clostridium difficult associated, diarrhea. It is approved by the U.S food and drug administration for the treatment of anaerobic infections, metronidazole exerts it antimicrobial effects through the production of free radicals that are toxic to the microbes, the use of metronidazole for treating specific infection is discussed separately.
Metronidazole is cytotoxic to facultative anaerobic bacteria such as helicobter pytori and Gardnerella vaginalis but the mechanism of this action is not well understood, however, its activity against obligate anaerobes occurs through a four step process.
Enity into the microorganism:-Metronidazole is a low molecular weight compound that diffuses across the cell membranes of anaerobic and anaerobic microorganism.
Reduction activation by intracellular transport proteins, metronidazole is reduced by the pyruvate, ferrodoxin ,oxidoreductase system in obligate anaerobic which alters its chemical structure, pyruvate,ferrodoxin,oxidoreductase normally generates adenosine Triphosphate (ATP) via oxidative decarboxylation of pyruvate with metronidazole in the cellular environment, its nitro group acts as an electron sink, capturing electrons that would usually be transferred to hydrogen ions in the cycle.
Reduced intermediate particule interacts with intracellular targets cytotoxic intermediate particules interact with host cell DNA resulting in DNAstrand breakages and fatal destabilization of the DNA helix.
Breakdown of cytotoxic-intermediate products: The toxic intermediate particles decay into inactive end
product.(9)
1.3.2 Resistance
Despite extensive worldwide use acquired resistance to metronidazole among anaerobic bacteria is rare. Anaerobic surveys demonstrates that more than 95% of anaerobic were isolated in the United States which are susceptible to metronidazole .(10) The second survey also found no resistance in 542 blood stream B. fragilis isolates from 12 United States medical center.
The antibiotic susceptibilities of subgingival flora were compared between the Netherlands and Spain, the incidence of resistance for number of antimicrobials including metronidazole was higher in Spain, a country in which system of antimicrobials are used more frequently.
1.3.3 Spectrum of Activity Of Metronidazole
Metronidazole is active against a broad array of anaerobes protozoa and micro aerophillic bacteria, metronidazole exert potent bactericidal activity against bacteriodes spp, Clostridium spp and bilophila wadsworthia, Clostridium spp are usually susceptible to metronidazole, although C. ramosium may require higher concentrations of the drug for inhibition. Among gram positive anaerobic bacilli 15% of antinomies spp, propiono bacterium propionica propioni bacterium acnes and lactobacillus species are resistant to metronidazole.(11)
1.3.3 Pharmacokinetics of Metronidazole
Systematically metronidazole is well absorbed after oral administration and is virtually 100% bio-available, it is generally well distributed into the body tissue and unlike clindamycin, which effectively penetrate the blood brain barrier in patient without inflammation, cerebrospinal fluid (CSF) levels approximate 45% of corresponding serum concentrations.
Metronidazole exhibits excellent penetration into brain abscesses, where concentration approximate in serum, metronidazole are also well distributed into muscle tissue of patient with sepsis or those undergoing surgery, metronidazole is minimally protein bound with approximately 80% or more circulating as free drug concentration sufficient for therapeutic activity are achieved in hepatic abscesses as well as alveolar bone.
1.3.4 Toxicity of Metronidazole (Flagyl)
The most common adverse effect associated with metronidazole is gastrointestinal. Gastrointestinal symptoms such as nausea, anorexia, vomiting, diarrhea, abdominal cramping and constipation have been with metronidazole, and unpleasant metallic taste is also often experienced by those taking metronidazole, nervous system, seizure, peripheral neutropathy, dizziness, vertigo, ataxia, convulsion, encephalopathy, irritability, weakness, insomnia, headache and tumors have been reported among patient receiving metronidazole particularly among those receiving high dose of the drug (12).
1.3.5 Half-Life of Metronidazole (Flagyl)
The half-life metronidazole in patient with normal renal function is 6-9 hours and is unchanged in those with renal insufficiency, some studies have demonstrated that elimination of metronidazole metabolites may be reduced among those with renal insufficiency but there no specific recommendations for dose reduction in patients.
Hemodialysis may increase the clearance of metronidazole by 100% or more resulting in a shortened half-life of only 2.1-3.3 hours. The pharmacokinetics of metronidazole and its metabolites are not appreciably affected by chronic ambulatory peritoneal dialysis with peritoneal dialysis accounting for only 8.9% of total body clearance, however the half-life of the drug may be extended to 18-20 hours in those with hepatic failure, the delay in elimination is directly related to the extent of liver impairment. Among children and adolescents, the pharmacokinetic of metronidazole are similar to those of adults. However, metabolic elimination of metronidazole is significantly decreased among premature neonates with clearance and half life correlating with gastrotional age, careful dose adjustments are those recommended for patient population .(13)
1.3.6 Topical Administered Metronidazole.
When metronidazole is being administered intraviginally the gel in metronidazole varies depending upon formulation. The commercial intraviginal gel produce peak serum concentration 0.2 to 0.3mgl /L which are significantly less than those observed after a single 500mg oral dose (8- 13mg/L).
1.4 METAL COMPLEXES
Metal are Lewis acids, because of their positive charge ion, most analytical reactions of organic reagents yields salts complex (coordination) compound. In complex formation, the central metabolism (action) reacts with available free electron pair on one of the atoms in their molecule i.e the donor atom, the ligands are able to coordinate with the central ion and to form a complex compound. Examples are the Cu+ which quickly becomes bounded to four water molecules to give a pale blue complexion with the formular (CuH20)2+ the water molecules provides the electron pairs with Cu2+ion, so water here is behaving as a lewis base by accepting a share of an electron pairs from each of the molecule. The Cu2+ion is behaving as a Lewis acid as the coordination number is defined as a number of ligands that is bounded to a given metal ion. Chelation compounds are coordination compounds in which a single ligand occurs more than one coordination position such ligands are called CHELATING AGENTS.
1.5 PROPERTIES OF LIGAND
Metronidazole (flagyl)
Molecular formular:C13H13N304
Molecular mass: 275moL-1
Structure
Mode of action of metronidazole(flagyl)
Metronidazole is a low molecular weight compound that diffuses across the cell membranes of anaerobic and aerobic microorganism, however antimicrobial activity is limited to anaerobe. Metronidazole is reduced by the pyruvate, ferrodoxin,oxidoreductase system in the mitochondria of anaerobes which alters it chemical structure, pyruvate, ferrodoxin, oxidoreductase normally generate adenosine triphospate (ATP) via oxidative decarboxylation of pyruvate with metronidazole in the cellular environment, its nitro group acts as an electrons that would usually be transfer to nitrogen ions in this cycle. Reduction of metronidazole creates a concentration gradients that drives uptake of more drug and promotes formation of intermediates compounds and free radicals that are toxic to the cell.
1.6 PROPERTIES OF IRON, BIOLOGICAL IMPORTANCE AND
TOXICITY
Iron has atomic number 26 electronic configuration 1S22P63S23P64S23d6, its atomic weight is 55.847, has a melting point of 1536oc and boiling point of 300oc. It has two common oxidation states of +2 and +3 ,Fe3+is the most stable because it has 3d5 electronic arrangement,. However solution containing Fe2+are ionized by air to Fe3+
Biological importance of Iron
Iron is present in meats especially liver and kidney, during growth iron is required for the formation of hemoglobin in the red blood cells and a number of other enzymes.
Toxicity of Iron
All Iron preparation ingested in excess can be equally toxic per unit of soluble ion. Symptoms include nausea and vomiting due to gastrointestinal irritation and necrosis, there may be a cyanosis lassitude, drowsiness, nematemisis and diarrhea. (16)
1.7 PROPERTIES OF NICKEL
Nickel has an atomic mass of 28 and with the electronic configuration of ls22s22p63s22p63d84s2.
Biological importance
Nickel is used as a catalyst to remove organic contaminate from waste water, also essential in animal nutrition, significant concentration of nickel has been shown to be present in DNA and RNA. (17,18)
Toxicity Of Nickel
Exposure of nickel carbonyl is the most hazardous of all individual exposure of nickel. It is toxic even in low concentration, initial symptoms to exposure including nausea, dizziness, headache and chest pain which disappear in few hour. (20)
1.8 PROPERTIES OF COBALT
Cobalt is a hard ferromagnetic silver-white, hard, lustrous, brittled element. It is a member of group VIII of the periodic table. Like iron, it can be magnetized. It is similar to iron and nickel in its physical properties. Cobalt is stable in air and unaffected by water, but is slowly attacked by dilute acids. It has an electronic shell of [Ar]3d74S2
Biological Importance of Cobalt
Cobalt is an essential trace element that is an integral part of vitamin B12, which is essential in the metabolism of folic acid and fatty acids. It involves the production of red blood cells and is important for the proper functioning of the nervous system as it can help in creating a myelin sheath.
Toxicity of cobalt
Though cobalt is an essential element for human health but the excessive intake level are poisonous and can cause significant health problems or even death. The side effect include vision or hearing loss, cardiomyopathy (weakening of the heart muscle), cognitive impairment and shortness of breath.
1.9 PROPERTIES OF MANGANESE
Manganese is a silvery-gray metal that resembles iron, it is hard and very brittle,difficult to fuse, but easy to oxidize, manganese metal and its common ions are paramagnetic. Manganese tarnishes slowly in air and oxidizes (“rusts”)like iron in water containing dissolved oxygen.[Ar]4s23d5
Biological importance of manganese
Manganese plays an important role as an enzyme activator in the human body such as Biotin, Thiamin, ascorbic acid and choline are some of these vital nutrients. It acts as catalyst in the synthesis of fatty acids and cholesterol. The metabolism of protein and carbohydrate is another one of its functions. It may also play a role in the production of sex hormones and in maintaining the reproductive health of an individual. Manganese helps in the production of thyroid hormone called thyroxine, which is responsible for controlling the rate of metabolism, regulating the rate of oxygen use by cells and generating body heat and helps in maintaining healthy nerve tissues
Toxicity of manganese
Excessive inhaling of manganese can result in a permanent neurological disorder known as manganism with symptoms that include tremors, difficulty in walking and facial muscle spasm.
1.10 AIM OF THE PROJECT
The aim of the project is to synthesize metronidazole (flagyl) metal complexes from the reaction of metronidazole (flagyl) with drug complexes of Ni(ii), Fe(ii), Co(ii), Mn(ii) salt and to characterized the complexes usind physical properties such as melting point determination and solubility test.
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