CHAPTER ONE
1.0 Introduction
Investigation on 4-acyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (4-acylpyrazol-5-one) and its transition metal complexes has attracted significant attention because of their applications as extractants1, antipyretic2, analgesic3, antitubercular4, antimycobacterial5, antibacterial6, antifungal7, and antineoplastic8 drugs. 4-acylpyrazol-5-one, is an enolizable ligand with strong ligating ability. These ligands are synthesized by direct acylation at C – 4 of 3-methyl-1-phenyl-1H-pyrazol (4H)-5-one (PMP) with acyl chloride or anhydrous pyridine in dioxane at reflux9. 4-acylpyrazol-5-ones are phototropic isomers forming ketoenol, diketo-, and aminodiketo tautomers10. These features of tautomerism imbues them with several coordination modes11 (O, O-donors, O, N-donors, O-donor) and easily form coordination compounds with virtually all the elements in the periodic tables. This ligating ability is more predominant with transition elements because of increased bonding orientation associated with the d-orbitals. Owing to their high extracting ability, lower pKa values (in comparison with acetylacetone, (acac–), and thenoyltrifluroacetone, (HTTA), great separation power, intense colour of complex extract, and low solubility in aqueous medium, several workers have used 4-acylpyrazol-5-ones to extract metal ions12. Based on their ligating properties they are also used in the spectrophotometric determinations of several metal ions such as Fe(III)13, V(VI)14 UO22+15 Mo(IV)16, Ni(II)17, Co(II)18, Mn(II)19, V(IV)20, Cr(VI)21, Ca(II)22, Zn(II)23, Mg(II)24. 4-acylpyrazol-5-ones such as acetyl-(HPMAP), propionyl-(PMPrP), Butyryl-(HpmBuP), isobutyryl-(Iso-HPMBuP), benzoyl (HPMBP), valeroyl (HPMVP), isovaleroyl- (HPMisoVP), caproyl (HPMCP) trifluoroacetyl (HPTFP), and trichloroacetyl-(HPTCP)25 have been synthesized, spectroscopically characterized, and used in diverse applications that cut across medicine26, biology27 and pharmacology28.
Because of their thermal stability29 these functionalized ß–diketones are used as molecular precursors in chemical vapour deposition techniques and in fabrication of polymer light-emitting diodes for low-cost, full-colour, flat-panel displays30. The magnetic and electronic properties of ß-dikotonates are also used in liquid crystals display and supramolecular assemblies31. As catalysts in hydroformylation and hydroboration, 4-acylpyrazolonates are used as spectator donors32 for intermediate species in organic reactions. Investigation of coordination compounds of lanthanide ions has been done by several worker owing to their fluorescent broad applications in biochemistry33, materials science34, and medicine35. 4-acylpyrazol-5-ones with a pyrazole nucleus share structural features with some pyrazol-5-ones derivatives (metamidozole, phenazone or antipyrine, dipyrone, edaravone) that exhibit as analgesic, antipyretic and anti-inflamatory activity36. Because of its promising antipyretic and analgesic activity, these drugs are used for treating fever and flu-like infections37. Edarovone (3-methyl-1-phenyl-2-pyrazolin-5-one) which has close resemblance to 4-acyl-pyrazol-5-one is used in the treatment of brain ischemia38 and myocardial ischemia39. Also, because of pyrazole functionality, 4-acyl pyrazolone exhibit cytoxic activity against bacterial40 and fungal pathogens41 and cancer cells42.
1.2 Statement of the problem
Though Jensen’s method of synthesizing 4-acylpyrazol-5-one using conventional heating method supplanted the method used by Claisen 100 years ago43, it still posed a great environmental problem44. These methodologies, although utilized for the preparations of a variety of pyrazol-5-ones, often require the use of refluxing conditions and lengthy reaction time, ideally 2-3hrs45. Moreover, the use of excess and often costly solvents and their recovery can pose a major environmental problem46 especially in the large-scale synthesis. Due to the increased environmental consciousness throughout the world, extensive efforts have been developed as an alternate synthetic approach for biological and synthetically important compounds. The microwave-assisted one-pot synthesis47 is one of the areas where substantial progress will be directed. Again, the scourge of infective diseases and increased pathogen resistance48 by bacterial and protozoal microorganism to existing drugs and in continuation of our search for biologically active molecules has necessitated the urgent need for novel drugs49 for treatment of Malaria and trypanosomiasis in human beings and cattle50. These devastating effects have called for alternative, effective regimen of chemotherapy51. Moreso, environmentally hazardous pesticides and insecticides used in our farms call for benign alternatives52. Keeping in view of these limitations of existing drugs we synthesize acylpyrazolonates that is both efficacious and bereft of blighting of our medicinal herbs in the farms.
1.3 Objective of the study
The debilitations and health hazard caused by exposure to pathogen such as bacteria, fungi, plasmodium, and trypanosomiasis, have necessitated the synthesis of drugs that will be used for effective treatment. The specific objective of the study therefore is to:
- synthesize 4-benzoyl-, 4-trifluoroacetyl-, 4-butyryl-, 4-propionyl, and 4-caproyl-3-methyl-1-phenyl-IH-pyrazol(4H)-5-ones;
- synthesized coordination compounds of Co(II), Ni(II), Pd(II), Fe(III), and Zr(IV) with the five ligands;
- characterize the ligands and the coordination compounds via spectroscopic methods: 1HNMR, 13CNMR, Mass spectrometry (MS), Fourier Transformed infrared spectrometry (FTIR) and ultraviolet spectrometry (UV), and elemental analysis;
- perform bioassay (antimicrobial, antimalarial, and antitrypanosomal) studies of the ligands and coordination compounds.
1.4 Justification
A cursory examination of previous work in the literature shows that little work has been done on the in vitro antimicrobial activity of 4-acylpyrasol-5-one, but so much work has been done on the synthesis, characterization of Schiff-base derivatives of 4-acypyrazol-5-one53. 4-acylpyrazolones have been used in the treatment of iron excess in over transfused patient or in hereditary iron overload disease and in iron intoxication. 1-phenyl-3-methyl-4-heptanoyl-5-pyrazolone shows limited inhibitory activity in vitro against some human pathogenic bacteria (B. subtilis, E.Coli, S. Epidermidis, and S. aureus). 4-formylpyrazol-5-one shows cytotoxic activity against S. aureus, E. Coli, P. aeuroginosa. Due to our interest in the synthesis, characterization of heterocyclic compounds of potential pharmacological significance, transition metal complexes of Co(II), Ni(II), Pd(II), Zr(IV), Fe(III) were screened, for the first time, for their antimicrobial, antimalarial, and antitrypanosomal cytotoxicity.
1.5 Background to the study
Human African trypanosomiasis (HAT) also known as sleeping sickness, is a vector-borne parasitic disease caused by infection with protozoan parasites belonging to the genus Trypanosoma. HAT is transmitted to humans by tsetse fly (Glossina genus) bites which have acquired their infection from human beings or from animals harboring the human pathogenic parasites. Human African trypanosomiasis takes two forms, depending on the parasite involved: Trypanosoma brucei Gambians is found in human beings in 24 countries in west and central African. This form currently accounts for over 98% of reported cases of sleeping sickness and cause a chronic infection54. Trypanosoma brucei rhodesience is found in 13 countries in eastern and southern Africa. This form represents fewer than 2% of reported cases and causes an acute infection55. Another form of trypanosomiasis occurs mainly in Latin America. It is known as American trypanosomiasis of Chagas disease. The causal organism belongs to a different Trypanosoma subgenus and is transmitted by a different vector. The type of treatment depends on the disease state. The drugs (pentamidine and suramin) used in the first stage are safer and easier to administer than those for second stage (melarsoprol and eflornithine). Treatment success in the second stage depends on drugs that cross the blood-brain barrier to reach the parasite. Such drugs are toxic and complicated to administer.
Malaria is an epidemic disease due to a parasite of the red blood cells called plasmodium and which is transmitted by mosquito (females called Anophele)56. It is a pandemic disease at the origin of major problems of public health for the population living in more than 40% of the world territory57-58. It is generally estimated that malaria is the leading cause of death in tropical Sub-Sahara countries of Africa. Malaria is a major public healt concern in the world, causing an estimated one million deaths per year. Approximately, half of the world’s population is at risk of malaria and the vast majority of cases (78%) occur in the African region. Even though the disease is preventable and curable, it is still one of the greatest global public health challenges especially in Sub-Sahara Africa. There is need for development of new antimalarial agents, due to the increasing resistance of the parasite to available agents. Development of antimalarial drugs can be from natural or synthetic origin. These developments can be achieved through many ways, ranging from minor modifications of existing drugs to the rational drug design of novel agents that act against new targets.
1.6 Scope of Present Investigation
The present research will involve the synthesis of four 4-acylpyrazol-5-ones and the Co(II), Ni(II), Pd(II), Fe(III) and Zr(IV) complexes. The 4-acylpyrazol-5-one ligands and the complexes will be characterized on the basis of elemental analysis, UV-VIS, FTIR, 1H NMR, 13C NMR, and electrospray mass spectrometry. Because of the possibility that the ligands will exist as tautomers, their coordination to the metal ion centers of Co(II), Fe(III), Pd(II), and Zr(IV) using O, O-, O, N-, and N,N- atoms will be investigated. Using IR,UV, 1H NMR, 13C NMR the structures of the ligands and complexes will be investigated. In addition, their pharmacological properties will be investigated. The ligands and complexes will be screened for their in vitro antimicrobial cytotoxic activity against three bacterial pathogens: (Gram-negative Escherchia coli, Gram-positive Staphylococcus aureus, and Bacillus subtilis; and fungal strains of Aspergillus niger and Candida albiicans by the agar well diffusion methods.
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