The introduction of heteroartoms in the pyrazine portion of the pteridine ring has produced compounds which display antifolate activity. The initial objective of this research program was to develop a convenient synthesis of the 8-oxadihydropteridine ring system and to test the resulting compounds for antifolate activity in suitable biological systems.

Call number: LD2668 .T4 1979 G55 / Master of Science

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg In fulfilment of the requirements for the Degree of Master of Science June, 30, 2015 / The world suffers under a serious threat of malaria with about 584 000 deaths reported each year and most of these fatalities being children under five years of age. Malaria is caused by the protozoan parasite of the genus Plasmodium. Five different malaria species infect humans and cause disease: P. vivax, P. malariae, P. ovale, P. knowlesi and the cause of most malaria deaths, P. falciparum. The main reason for this disturbing situation is the emergence of drug resistance which reduces the effectiveness of most antimalarials. Hence, there is an urgent need for new drugs that will possibly be effective against both wild type and mutant strains of Plasmodium species. Pyrimethamine, a dihydrofolate reductase (DHFR) inhibitor, has been used most widely as an antimalarial antifolate drug for the treatment of malaria. However, rapid development of parasite resistance to this drug occurred because of its rigidity. Parasitic resistance to antimalarial antifolates arises from single mutations at various amino acid residues surrounding the PfDHFR active site. In this project, we aimed to design and synthesise a novel series of flexible pyrimidine analogues of a dihydrotriazine hit compound prepared in a previous study. These compounds were designed to target folate metabolism in the malaria parasite. The initial series of compounds prepared in this project were synthesised over 5 steps in an overall yield of 10%. The flexible pyrimidine analogues were screened for antimalarial activity in an in vitro P. falciparum screen on the Gambian FCR-3 strain (chloroquine and cycloguanil resistant strain) with dihydroartemisinin, methotrexate and quinine as controls. 5-(3-(3,5-Dichlorophenoxy)propyl)-6-phenylpyrimidine-2,4-diamine displayed the best antimalarial activity (IC50 = 0.09 μM) of the compounds in this series. Surprisingly; this was the only compound prepared in this series that proved to be as effective as our original hit dihydrotriazine (IC50 ~50 nM). In the second generation of compounds prepared in this study, we used a multicomponent coupling approach to synthesise three flexible pyrimidines bearing a non-aromatic side chain at the 6-position of the pyrimidine ring. For comparison, two analogues bearing a phenyl group at the 6-position of the pyrimidine ring were also prepared. Once again; only one compound of this series [5-((4-chlorophenethylamino)methyl)-6-cyclopropylpyrimidine-2,4-diamine, (IC50 = 0.03 μM)] showed activity comparable with our original hit compound. iv Finally, ten substituted pyrimidines bearing a flexible side chain at the 6-position of the pyrimidine ring, were prepared. These compounds are structurally similar to P65, [6-methyl-5-(3-(2,4,5-trichlorophenoxy)propoxy)pyrimidine-2,4-diamine] an analogue of a potent antifolate, WR99210, found to have good oral bioavailability in rats. Once again, the antimalarial activity of the compounds prepared was assessed in an in vitro P. falciparum screen on the Gambian FCR-3 strain. The most promising compound of this series was 6-(3-(3,4-dichlorophenoxy)propoxy)pyrimidine-2,4-diamine, which exhibited antimalarial activity in the low micromolar range (IC50 = 4.46 μM).

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Purpose: Anemia in children is a major Public Health problem in developing countries such as Ivory Coast. The fortification of wheat flour with iron and folic acid has been mandated in this country in 2007. To date, there are no studies conducted to assess the effectiveness of these fortification efforts. Therefore, the purpose of this study was to determine if mandated iron and folic acid fortification of wheat flour has reduced the prevalence of anemia in Ivory Coast children. Methods: The study was conducted at the pediatric unit of the university hospital of Treichville, one of the 3 main hospitals of Abidjan, the largest city of Ivory Coast. The medical records of 467 children from 5 to 14 years old were analyzed. The period from January 1st 2004 to December 31st 2006 was considered as pre-fortification period and the period from January 1st 2008 to December 31st 2010 was regarded as the post-fortification period. Data for anemia, hemoglobin, hematocrit, red blood cell count, and MCV were compared between pre- and post-fortification periods. Results: The results showed that there were no statistically significant difference in prevalence of anemia and mean hemoglobin, hematocrit, red blood cells, and MCV between pre and post-fortification periods. Conclusion: The double fortification of wheat flour with folic acid and iron had no significant impact on anemia in Ivorian children. This is perhaps due to the fact that wheat flour is not widely consumed as rice and rice products are more popular in Ivory Coast population. The Ivorian government perhaps should focus efforts on the fortification of these products.

It is highly recommended for women to take multivitamin/mineral supplements during the periconceptional and prenatal periods. Studies have confirmed that taking prenatal multivitamins prevents maternal iron deficiency anemia, and reduces the risk for neural tube defects (NTDs). To date, research aimed at optimizing the use of multivitamins before and during pregnancy has been minimal. My thesis focused on two challenges of periconceptional and prenatal multivitamin supplementation. The first challenge was gastrointestinal (GI) adverse events such as nausea and constipation which may be attributed to iron content and tablet size. Pregnant women are highly susceptible to GI adverse events since 80% experience nausea and vomiting of pregnancy. A prospective, randomized, controlled, open-label study was conducted to investigate whether a low-iron, small-tablet prenatal multivitamin can reduce GI adverse events, and improve supplement tolerability and adherence, relative to a high-iron, small-tablet prenatal multivitamin. We determined that low iron dose did not produce a significant difference, while small tablet size could be considered an important factor. Moreover, our results confirmed that adherence was poor in pregnant women. We were prompted to identify determinants which could predict adherence to prenatal multivitamins. Our retrospective study determined that predictors of adherence are rooted in women’s prior experiences with multivitamin use. The second challenge we addressed was achieving adequate blood folate concentrations for prevention of NTDs. If adherence is poor, standard dosing of 0.4-1 mg folic acid may not produce the blood folate concentrations needed in women prior to conception. We investigated the pharmacokinetics of 5 mg folic acid. Our prospective, parallel, open-labeled study, comparing a single dose of 5 mg to 1.1 mg folic acid, confirmed that folic acid follows linear (proportional) pharmacokinetics. However, our prospective, randomized, controlled, open-labeled, multiple-dose study determined that repeated use of folic acid at these 2 doses followed non-linear pharmacokinetics. Nevertheless, our data confirmed that 5 mg folic acid can produce higher blood folate concentrations, with a faster rate, which can counter the effect of poor adherence. In conclusion, optimal use of prenatal multivitamins requires improvements in supplement tolerability, adherence, and pharmacokinetics which depend on supplement formulations, and individualized assessment and counseling.

Folate intake in North America has drastically increased over the past decade due to folic acid fortification and widespread supplemental use. The role of folate in breast cancer is highly controversial and the effects of folic acid supplementation on breast cancer patients are currently unknown. An animal study was performed to determine the effects of folic acid supplementation on the progression of the mammary tumors in the DMBA-carcinogen model. Folic acid supplementation was associated with more rapid sentinel tumor progression and with higher sentinel tumor weight, volume, and area, although no clear dose-responsive relationship was observed. Folic acid supplementation was associated with an increased expression of proapoptotic protein PARP and decreased expression of proliferation protein PCNA. These data suggest that folic acid supplementation may promote the progression of established mammary tumors. Whether or not folic acid supplementation may adversely affect the outcome of patients with breast cancer warrants further studies.

Folate blood levels in North America have dramatically increased over the past decade owing to folic acid (FA) fortification and widespread supplement use. Furthermore, over 50% of newly diagnosed colorectal cancer (CRC) patients use vitamin supplements containing FA while receiving chemotherapy whose mechanisms of action are based on interruption of folate metabolism. This study therefore investigated whether FA supplementation can affect chemosensitivity of human colon cancer cells to 5FU, the cornerstone of CRC treatment, using a xenograft model. FA supplementation was associated with a non-dose dependent decrease in chemosensitivity, where mice receiving 8 mg FA did not respond to 5FU and had greater tumor growth with treatment, compared to 2 (control) or 25 mg FA. Results of this study pose concern given the drastically increased intake of FA, particularly among recently diagnosed CRC patients, and from mandatory fortification. Further studies are warranted to confirm our findings and to elucidate underlying mechanisms.