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CJ1iere is the joy of origin.. of receiving and the joy of present remembrance. I would like to thank my mentor Prof.GA.Kolawole for his invaluable contribution to the success of this study, for his guidance and support throughout the work and for his encouragement to come to study at the University of Zululand in the first place. Paul O'Brien, Head of the Faculty of Chemistry, University of Manchester, UK, for hosting me in his group and for his constructive suggestions.

Reto Brun from the Swiss Tropical Institute, Switzerland and his assistant Marcel Kaizer for screening the complexes against isolates of Plasmodium falciparum. I express my sincere gratitude to the University of Ado-Ekiti, Nigeria for allowing me to conduct this study and the entire staff and students of the Department of Chemistry, University of Ado-Ekiti. The synthetic techniques were based on the modification of antimalarial drugs by introducing metal ions into the molecular structure of the substances.

Six of the complexes and sulfadiazine ligand were also characterized by single X-ray crystal studies. Synthesis of the platinum(II) complex of chloroquine 67 2.9 Synthesis of the iron(IIl) complex of pyrimetharnine with dithiocarbarnate Synthesis of the iron(lll) complex of pyrimetharnine with trimethoprim 68 2.92 Synthesis of the cobalt(ll) complex of pyrimethamine with trirnethoprim 68.

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INTROD UCfION AND LITERATURE REVIEW .1 Introduction

• Immunity
• Treatment of Malaria
• Chemical Classification
• Combination Therapy

Malaria infections are caused by intracellular parasites of the genus Plasmodium, which are transmitted by Anopheles mosquitoes (Figure I). The retardation of long-term national, regional and continental economic growth rates due to malaria has only recently been appreciated. Four species of the parasite, namely Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax and Plasmodium ovaIe, infect humans.

Differentiation of species depends on the morphology and staining of associated changes in the containing cells. The immune status of the individual and the population plays the most important role in the clinical response to infection and transmission. It was also demonstrated that an indirect hemagglutination test could serve as a measure of protective immunity. The fluorescent antibody technique also revealed that many different species of mammalian Plasmodium share a common antigen.

The gametocytocides act on the potentially sexual forms, the gametocytes, which are able to ensure the transmission of the disease to anopheles and thus maintain malaria endemicity. They work on the liver cells (pre-erythrocytic stage) to prevent the invasion of the red blood cells e.g.

Primaquiue

Pamaquine

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Proguanil

Chloroproguanil

• Antimalarial Drugs from Plants
• Malaria Vaccine
• A Review of Metal-Based Malaria Chemotherapy
• Objectives ofthe project
• Synthesis of lron(Ill) complex of pyrimethamine with trimethoprim
• Synthesis of cobalt(ll) complex of pyrimethamine with trimethoprim
• Infrared Spectra
• Cobalt (III) complexes of Trimethoprim
• Infrared spectra ofthe complexes
• Ni(ll), Pd(ll), and Pt(ll) complexes of Sulfadiazine
• Oxovanadium(lV) complex ofsulfadiazine
• Metal Complexes ofTrimethoprim
• Cobalt(Il) Complex oftrimethoprim
• Electronic Spectra and Magnetic properties ofthe Co complexes
• Infrared Spectra ofPt(ll) and Pd(ll) trimethoprim complexes
• Nickel (II) complex of Trimethoprim
• lron(lll) complex of Amodiaquine with 2,2-bipyridine
• Platinum (II) complex of Chloroquine
• Biological Studies 4.1 Introduction
• Results and Discussion

It has also played a significant role in the occurrence and severity of epidemics in some parts of the world69•The factor that limits success in the use of antimalarial drugs for prophylactic or curative purposes is the varying response of different strains of the parasite to drugs. The biochemical mechanism of resistance has been well described for chloroquine, f the antifoliate combination drugs,73 and atovaquone". In recent years, the burden of disease and mortality has increased significantly in malaria-endemic countries. P' and transmission has spread to new areas152• The main causes of this resurgence are the development of resistance to affordable drugs153 and insecticides,154 deterioration of national control programs/55 increasing human migration/56 and tourism157.

The resulting cream-colored solution was refluxed for 2 hours. The product was filtered and the filtrate was allowed to evaporate slowly at room temperature. Trans-andcis-[Co(en}zClz]CI was synthesized as starting material for the synthesis of cobalt(lII) complexes of the antimalarials. Cobalt(lIl) complexes are expected to be diamagnetic. The effective magnetic moments appear slightly higher than what is expected from low-spin octahedral d6 configuration.

In the solution spectrum, the complex showed absorption bands in the region of 16,475 em" (607 nm) which appear slightly split and can be attributed to IA lg-+'r., The. IR band assignments are suggested based on the reported detailed IR study data and vibrational assignments for tetracycline and analogs and other studies of metal-tetracycline complexes I611•The infrared spectra of the two complexes are similar. The complexes were non-electrolytes in OMF with Am values ​​of 1.0 and 4.0 n-1cm2mor l• The.

The analytical data for the complexes are presented in Table 3. The proposed octahedral geometry for the complexes consists of a metal ion coordinating to two molecules of sulfadiazine that act as bidentate ligands through a pyrimidinyl N and sulfonamido N atoms on each sulfadiazine molecule. Co(SD)z(HzO)z] gave an additional intense band at 426 em-I which is completely absent in [Co(SD)z(CH 3 O H)z]. The involvement of N and 0 in the coordination is further strengthened by the appearance of bands at 590-297 cm-I assigned to v(Co-N+ Co-Q). However, due to strong Jahn-Teller distortion, octahedral Cu(II) complexes often give broad bands due to multiple overlapping bands or, where the bands are resolved, up to three close bandsI65• The electronic spectrum of the Cu(II) sulfadiazine complex in Figure 29 shows a broad asymmetric band in the regions cm'1 (525-625 µm).

Further confirmation of the stereochemistry obtained from the magnetic susceptibility measurements showed that the complex has an effective magnetic moment of 1.88 B.M. Thus, it could be concluded that the complex has a distorted octahedral geometry, since the E fundamental term in octahedral coordinated ions gives moments greater than the spin-only value due to the mixing of the excited T term in the fundamental term, and the high value on. the spin-orbit coupling constant) makes the effect significant. Thus, the states 4Alg, 4Azg, and 4Eg have energies independent of any crystal field, and will appear as a horizontal line165• The electronic spectra of the Mn(II) complex of sulfadiazine are shown in Figure 25. The length of the Cu-- Cu binding is in the range of those reported in the literature, but slightly less than for copper-trimethoprim complex reported by Naldini, et al.113 • The packing schemes for the complexes are shown in Figures 49 and 50.

A microassay developed by Richman and adopted by the WHO for the epidemiological monitoring of drug-resistant malaria requires counting parasites under a microscope to measure the capacity of antimalarial drugs to inhibit the maturation of the parasite to the schizont stage179 • Results are expressed as minimum inhibitory concentration (MIC). The activity of test compounds is evaluated by comparison with compounds belonging to the same chemical class or compounds from different chemical classes19 1• Limitations of in vitro screening include the lack of information on drug metabolism, pharmacokinetics and drug toxicity. The in vivo test most accurately reflects actual clinical or epidemiological situations203• The original methods for in vivo tests required longer follow-up periods (at least 28 days) and isolation of patients in examined rooms to prevent the possibility of re-infection.

In sub-Saharan Africa, the method currently used and promoted is a system that emphasizes clinical response rather than parasitological response207• WHO has developed guidelines for in vivo testing of antimalarial drug efficacy against Pofalciparum and P.vivax in areas with .