ABSTRACT
Copper, magnesium and zinc complexes of acetaminophen were synthesized and characterized by infrared spectroscopy, UV- Visible spectroscopy, melting point, X-Ray diffraction analysis and conductivity measurements. On the basis of this study, it is proven that acetaminophen acts as a bidentate ligand coordinated to the metal ions through phenol and carbonyl oxygen atoms. Antibacterial and antifungal activities of the complexes were determined against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa and Candida albicans. The results indicate that acetaminophen showed activity against Pseudomonas aeruginosa (18 mm and 15 mm) and Staphylococcus aureus (20 mm, 17 mm, 14 mm and 10 mm) respectively. Zinc complex of acetaminophen also showed activity against Pseudomonas aeruginosa (20 mm, 15 mm and 12 mm). Magnesium complex of acetaminophen showed activity against Staphylococcus aureus (19 mm, 15 mm and 13 mm), Salmonella typhi (15 mm and 12 mm) and Pseudomonas aeruginosa (27, 18 and 13 mm). Copper complex of acetaminophen showed activity against Staphylococcus aureus (23 mm, 20 mm, 17 mm and 15 mm), Bacillus subtilis (21 mm, 18 mm, 16 mm and 14 mm), Escherichia coli (22 mm, 19 mm, 17 mm and 14 mm), Salmonella typhi (18 mm, 16 mm, 14 mm and10 mm) and Pseudomonas aeruginosa (24 mm, 21 mm, 19 mm and 16 mm). Acetaminophen, magnesium and zinc complexes of acetaminophen showed the same inhibitory activity (50 mg/mL) against Pseudomonas aeruginosa. Zinc and magnesium complexes showed the same inhibitory strength (50 mg/mL) against Staphylococcus aureus. Copper complex of acetaminophen was found to be the best as it exhibits the lowest minimum inhibitory concentration (12.5 mg/mL). The lethal dose determination (LD50) of zinc, copper and magnesium complexes of acetaminophen were 289 mg/kg, 3808 mg/kg and 1265 mg/kg respectively. The complexes of copper and magnesium were considered slightly toxic while zinc
xviii
complex of acetaminophen was considered moderately toxic. Anti-inflammatory activity of the synthesized complexes has been carried out by paw edema method in rats. The maximum percentage anti-Inflammatory effects of zinc, magnesium and copper complexes of acetaminophen were 26.9%, 18.9% and 32.4% respectively.
TABLE OF CONTENTS
Cover page i Fly leaf ii Title page iii Declaration iv Certification v Dedication vi Acknowledgements vii Table of Contents viii List of Tables xiv List of Figures xvi List of Appendices xvii
Abstract xviii CHAPTER ONE 1
1.0 I NTRODUCTION 1
1.1 Acetaminophen and its Properties 1
1.2 Disease-causing Micro-organisms 2
viii
1.3 Importance of Metal-Based Complexes 2 1.4 Statement of Research Problem 3 1.5 Justification 3 1.6 Aim 4 1.7 Objectives 4 CHAPTER TWO 5 2.0 LITERATURE REVIEW 5 2.1 Medications that Contain Acetaminophen as their Active Ingredient 5 2.2 Chemical Properties of Acetaminophen 5 2.3 Maximum Daily Limit of Acetaminophen 6 2.4 Health Effects of Acetaminophen 7 2.5 Coordination Complexes 8 2.6 Microorganisms 9 2.6.1 Bacteria 9 2.6.2 Fungi 13 2.7 Antimicrobials 15 2.8 Antifungals 16
ix
2.9 Inflammation and Non-steroidal Anti-inflammatory Drugs 17 2.9.1 Types of Inflammation 17 2.9.2 Non-steroidal anti-inflammatory drugs 18 2.10 Role of Metals in the Body 19 2.11 Properties of Metal Ions and Metal-Based Complexes 20 2.11.1 Metal Complexes as Antimicrobial Agents 20 2.11.2 Synthesis and Characterization of Transition Metal Complexes of 4-Amino-5- Pyridyl-4h-1,2,4-Triazole-3-Thiol 21 2.11.3 Synthesis and Characterization of some Transition Metal Complexes Derived from Bidentate Schiff Base Ligand 22 2.12 Applications of Transition Metal Complexes in Drugs and Cosmetics 23 2.13 Antibacterial Properties of Some Heteroleptic Metal (II) Complexes of Paracetamol and Vanillin 24 2.14 Antimicrobial Properties of Ibuprofen Analgesic Drug Complexes with Certain Metal Ions 26 2.15 Antimicrobial Activities of Some Mixed Drug Metal (II) Complexes of Sulfamethoxazole and Paracetamol 28 2.16 In Vitro Antibacterial Activity of Ibuprofen and Acetaminophen 29
2.17 Antibacterial Activity of a Zn (II) Coordination Polymer Based on a
x
Paddle-Wheel Cluster 30 2.18 Antimicrobial, antioxidant and DNA cleavage studies of Cu(II) complexes of formyl chromone Schiff bases 31 2.19 Anti-Inflammatory and Analgesic Activities of Complexes of Zn (II) With 1,10- Phenanthroline and some Amino Acids 32 2.20 Metal Complexes Used as Anti-Inflammatory Agents 33 2.21 Antifungal Activity of Organometallic Complexes of Cholic Acid 34 CHAPTER THREE 36 3.0 MATERIALS AND METHODS 36 3.1 Materials 36 3.2 Preparation of Solid Complexes 36 3.3 Physical Measurement 37 3.3.1 Magnetic susceptibility 37 3.3.2 Unit Cell Parameters of the Metal Complexes 38 3.4 Antimicrobial Activity 39 3.4.1 Test Organisms 39 3.4.2 Culture Media 39 3.4.3 Turbidity standard for inoculum preparation-McFarland standard 39 3.4.4 Determination of Inhibitory Activity (Sensitivity test) of Acetaminophen and the metal complexes using Agar Well Diffusion Method 40
xi
3.4.5 Determination of Minimum Inhibitory Concentration of Acetaminophen and the Metal Complexes against the selected Bacterial and Fungal Isolates 41 3.4.6 Determination of Minimum Bactericidal Concentration of Acetaminophen and the Metal Complexes against the selected Bacterial and Fungal Isolates 41 3.5 Acute Toxicity Studies 42 3.6 Anti-inflammatory study 42 3.6.1 Statistical Analysis 43 CHAPTER FOUR 44 4.0 RESULTS 44 4.1 Physical Measurement 44 4.2 Anti-Microbial Activity of Metal-Acetaminophen Complexes 51 4.3 Minimum Inhibitory Concentration of Acetaminophen and Its Complexes 51 4.4 Acute lethal and Anti-inflammatory effects of Zinc, Copper and Magnesium Complexes 51 CHAPTER FIVE 66 5.0 DISCUSSION 66 5.1 Infrared Spectra of Acetaminophen and Its Complexes 67 5.1.1 Infrared Spectra of Mg(II)-AC Zn(II)-AC and Cu(II)-AC 67 5.2 Unit Cell Parameters of the Metal Complexes 68 5.3 Proposed Structure of the Synthesized complexes 68
xii
5.4. Antimicrobial activity of Acetaminophen, Zn(II)-AC, Mg(II)-AC and Cu(II)-AC against the Test Microorganisms 70 5.5 Susceptibility of Ciprofloxacin, Fluconazole, Copper Chloride, Magnesium Chloride and zinc chloride against the Test Microorganisms 71 5.6 Minimum Inhibitory Concentration and Minimum Inhibitory Concentration of Acetaminophen, Ciprofloxacin, Fluconazole, Cu(II)-AC, Zn(II)-AC and Mg(II)-AC 72 5.7 Acute Toxicity 73 5.8 Anti-inflammatory Activity 75 CHAPTER SIX 77 6.0 CONCLUSION AND RECOMMENDATIONS 77 6.1 Conclusion 77 6.2 Recommendations 77 REFERENCES 79 APPENDICES 90
CHAPTER ONE
1.0 INTRODUCTION
1.1 Acetaminophen and its Properties
Acetaminophen, also known as Paracetamol, is a medication used to treat pain and fever. It is typically used for the relief of mild to moderate pain reliever (Meremikwu, and Oyo-Ita, 2002). It is often sold in combination with other ingredients such as cold medications and combination with opioid pain medication. Acetaminophen is also used for more severe pain such as cancer pain and pain after surgery (Hochhauser, 2014). The chemical name of acetaminophen is para-acetyl aminophenol, and this is where acet-amino-phen comes from. Scientists or medical professionals refer to acetaminophen by using APAP (Larson et al., 2005). Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Acetaminophen is the most commonly used drug ingredient in America (FDA, 2012). More than fifty years of consumers use and scientific investigation has established acetaminophen as safe and effective when used as directed at recommended doses. However, like any medicine, there is a limit to how much should be taken in one day. The maximum daily dose of acetaminophen is 4,000 milligrams (US FDA, 2012). Acetaminophen is typically used orally, or rectally, and it is used intravenously. It can also be used in the hospital health service. For example, in the postoperative pain therapy, it has been shown that administration of intravenously paracetamol especially during the first hour of treatment is more efficient in reducing pain intensity than given orally. This is done to quickly decrease high fever or in the case when another route of administration is not possible (Pasero and Stannard, 2012).
2
1.2 Disease-causing Micro-organisms Microorganisms are the causative agents (pathogens) in many infectious diseases. The organisms involved include pathogenic bacteria, causing diseases such as plague, tuberculosis and anthrax; protozoa, causing diseases such as malaria, sleeping sickness, dysentery and toxoplasmosis; and fungi, causing diseases such as ringworm, candidiasis and histoplasmosis (Eckburg et al., 2006). While some microbes play an important part in our daily lives by keeping us healthy, others are nothing but bad news. These “bad-news” microbes are called disease-causing microbes and can make humans, animals and plants sick by causing infection and disease. Most microbes belong to four major groups: bacteria, viruses, protozoa or fungi. Disease-causing microbes can also be called pathogens, germs or bugs and are responsible for causing infectious diseases (Ishige et al., 2005). 1.3 Importance of Metal-Based Complexes
Metal-based complexes offer a rich environment to build upon a variety of distinct molecular structures that confer a wide spectrum of coordination numbers and geometries, as well as kinetic properties, that cannot be realized with conventional carbon-based compounds (Cohen, 2007). The partially filled d-orbitals in transition metals impart interesting electronic properties that can act as suitable probes in the design of anticancer agents (Hambley, 2007). The oxidation state of a metal is also an important consideration in the design of coordination compounds, given that it allows the participation in biological redox chemistry and plays an influential role in optimal dose and bioavailability of the agent administered (Thompson and Orvig, 2003). Furthermore, the ability to undergo ligand-exchanged reactions offers a myriad of opportunities for metals to interact and coordinate to biological molecules. Furthermore, when designing metal-based therapeutics, one is not restricted solely by metals selected by nature and can take advantage of the unique properties of
3
nonessential metals, including other 1st and 2nd row transition metals and metals that can impart additional utility not found naturally (Haas and Franz, 2009). Most notable is the design of radio-pharmaceuticals that exploit the radioactive properties of metals that are commonly used in the diagnosis of cancer and other medicinal applications (Haas and Franz, 2009). 1.4 Statement of Research Problem Literature data contain numerous references on the synthesis, characterization, and antibacterial activities of paracetamol complexes with some metal complexes (Sadler and Zijien., 1998; Lawal and Obaleye., 2007; Adediji et al., 2011; Bamigboye et al., 2012;Refatet al., 2013; Harminder et al., 2013; Osowole et al., 2013a; Osowole et al., 2013b). Most researchers obtained paracetamol tablets from pharmaceutical stores. Paracetamol tablets contain excipients, which may affect the characterization of the metal complexes. Synthesis, characterization, antimicrobial and anti-inflammatory activity of Complexes derived from Acetaminophen were less studied. There are some analgesics (Acetaminophen) that are commonly associated with anti-inflammatory drugs but that have no anti-inflammatory effects (Ottani et al., 2006; Dani et al., 2007) 1.5 Justification
Coordination complexes in which the Centre is a metal atom are gaining increasing importance in the design of drugs when the drugs (ligand) form complexes with metals. In spite of a large number of antimicrobial and chemotherapeutic drugs available for medical use, the emergence of new antibiotic resistance created in the last decades revealed a substantial medical need for new classes of antimicrobial agents. There is need for the discovery of new compounds with antimicrobial activity, which is distinct from those of well-known classes of antimicrobial agents to which many clinically relevant pathogens are now resistant. Therefore, it was necessary to study Acetaminophen-metal complexes, because of their analgesic, antipyretic and chemotherapeutic properties. We hereby report
4
the synthesis and characterization of acetaminophen with Mg(II), Zn(II), and Cu(II)complexes and the determination of their antimicrobial and anti-inflammatory properties. 1.6 Aim The aim of this research was to synthesize, characterize and to investigate the antimicrobial and anti-inflammatory properties of Mg(II), Zn(II), and Cu(II)as the central atoms using acetaminophen as the complexing agent or ligand. 1.7 Objectives The objectives of the study were to: I prepare of the solid complexes of Mg(II), Zn(II), and Cu(II)ions of acetaminophen; II characterize the metal-acetaminophen complexes using UV-Vis spectrometer, Infrared Spectroscopy, magnetic susceptibility and molar conductance; III estimate the crystallite size of the complexes using X-Ray diffractometer; IV determine the antimicrobial activity of the solid complexes of Mg(II), Zn(II), and Cu(II) ions of acetaminophen on bacteria and fungi; V investigate the acute toxicity of the solid complexes of Mg(II), Zn(II), and Cu(II) ions of acetaminophen; VI investigate the anti-Inflammatory property of the solid complexes of Mg(II), Zn(II), and Cu(II) ions of acetaminophen.
Do you need help? Talk to us right now: (+234) 08060082010, 08107932631 (Call/WhatsApp). Email: [email protected].
IF YOU CAN'T FIND YOUR TOPIC, CLICK HERE TO HIRE A WRITER»
