Scientific Research in School Volume 3 Issue 1 2021
Optimising the synthesis of the 4-iodo analogue of pyrimethamine Maxine Wu Barker College The emergence and rapid spread of drug resistant P. falciparum, the most prevalent malaria pathogen, has threatened to curtail the efficacy and therapeutic lifetime of antifolate drug treatments like pyrimethamine, due to point mutations in the dihydrofolate reductase (DHFR) enzyme of the parasite. Currently, the burden of malaria is highest in developing counties, and the deteriorating efficacy of existing anti-malarial drugs have increased the cost and complexity of routine prophylaxis and treatment. The present work proposes to overcome such resistance, using a simple rational drug design strategy which focuses on changing substituents on the pyrimethamine ring to synthesise new pyrimethamine analogues as potential drug leads. This report discusses methods used to successfully optimise the synthesis of the 4-iodopyrimethamine analogue and its possible future applications in cross-coupling reactions. Literature Review Malaria is a protozoan disease that continues to present major public health concerns for most endemic areas of the world (Weiss et al., 2019). Once infected, malaria attacks the body’s red blood cells, and if not treated within 24 hours, severe complications often lead to death (WHO, 2020). The burden of malaria is highest in developing countries, affecting vulnerable and marginalised populations – particularly children, pregnant women, migrants and refugees (Murphy, 2006). The optimisation of access to malaria intervention is essential for achieving universal health coverage and promoting well-being of all ages, having the potential to alleviate poverty, improve equity, hence contributing to overall socio-economic development in affected areas.
Globally, there were 229 million cases of malaria in 2019, with an estimated death toll of 409,000 (WHO, 2020). Of the five Plasmodium parasite species, Plasmodium falciparum is the most virulent causative agent, and in 2018, accounted for 99.7% of cases in the African region, 71% in the Eastern Mediterranean, 65% in the Western Pacific and 50% in the South-East Asian region (Figure 1). Since 2000, the scale-up of malaria control interventions has fuelled bold aims for disease eradication, having significantly reduced global morbidity and mortality (Weiss et al., 2019). This was driven by several factors, in particular, increased funding, effective vector control, and improved case reporting and surveillance (Cotter, Sturrock & Hsiang, 2013). Although remarkable
Figure 1: Spatial distribution of P. falciparum incidence (Source: Weiss et al., 2017) Science Extension Journal • 151
