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Malaria remains one of the deadliest human infectious diseases. In 2020 alone, there were an estimated 241 million clinical cases of malaria which resulted in approximately 627,000 deaths. With 3.2 billion people at risk of malaria and a global agenda focused on eradication there is a desperate need to improve malaria prevention and control strategies. As there is no highly effective vaccine, the treatment and prophylaxis of malaria are dependent on chemotherapy which is associated with increasing levels of parasite resistance. Given the lengthy development times for new drugs, strategies to safeguard current drugs are essential. This includes the development of resistance monitoring strategies and the rational selection of combination partners which should ideally be guided by mode of action information. The antimalarial drug proguanil is used in combination with the cytochrome bc1 inhibitor atovaquone (as Malarone®) for malaria prevention and treatment. While proguanil was developed as a pro-drug and is metabolized in vivo to the potent dihydrofolate reductase (DHFR) inhibitor cycloguanil, recent studies in our laboratory have demonstrated that it, and a cyclization-blocked analogue (tBuPG) that cannot be metabolized to cycloguanil, have potent slow action antiplasmodial activity independent of cycloguanil. Data has demonstrated that this activity is different to other slow action antimalarial agents and preliminary unpublished metabolomics work has shown that deoxythymidine monophosphate (dTMP) accumulates in proguanil and tBuPG treated parasites raising the hypothesis that P. falciparum thymidylate kinase (PfTMPK), the enzyme responsible for conversion of dTMP to deoxythymidine diphosphate (dTDP) may be a target of proguanil. However, the mechanism of proguanil’s slow action activity remains unknown. As proguanil’s intrinsic slow action activity may have clinical implications and there have been recent reports of resistant P. falciparum parasites in Uganda, the, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Full Text

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Environment and Sc, Science, Environment, Engineering and Technology, Giardia are a genus of enteric pathogens consisting of at least six species (Monis et al. 2009), of which one, Giardia duodenalis, infects humans (Heyworth 2016). In addition to humans, G. duodenalis parasites infect other mammals, which may act as reservoirs for human infection (Traub et al. 2004; Yaoyu and Xiao 2011; Abeywardena et al. 2015; Sroka et al. 2015; Štrkolcová et al. 2015; Heyworth 2016). In humans Giardia infection can be asymptomatic, however all infected hosts shed cysts and can transmit parasites (Oliveira-Arbex et al. 2016; Figgatt et al. 2017). Giardia infection can cause giardiasis, a diarrhoeal disease with a variety of clinical manifestations (Wolfe 1992; Homan and Mank 2001; Sahagún et al. 2008; Nielsen et al. 2014). An estimated 180 million symptomatic human Giardia infections occur every year (Kirk et al. 2015), and treatment is reliant on a small number of chemotherapeutic classes, all of which are associated with liabilities. Liabilities include but are not limited to; poor treatment efficacies, long treatment courses and side-effects which impact compliance (Cina et al. 1996; Wright et al. 2003; Escobedo and Cimerman 2007; Nabarro et al. 2015). Growing parasite resistance to the first-line treatment drugs, the 5-nitroimidazoles, is also a concern (Nabarro et al. 2015). The aim of the current study was to pave the way towards improved treatment options for giardiasis by identifying new lead compounds for drug development, and to further examine the activity of these compounds. To achieve this, a new anti-Giardia activity assay to assess parasite growth in micro-titre plates under microaerobic (3 % O2) conditions was developed. This image-based assay uses bright-field microscopy paired with digital phase-contrast microscopy and supervised machine learning software, PhenoLOGIC and Harmony® (Perkin-Elmer, USA) to differentiate and enumerate parasites. Growth assessment does not require cell-staining or a genetically modified parasite line, th

This review covers the work published in the calendar year 2013. Novel reaction chemistry and new ring synthetic methods for azepines, benzoazepines, oxepines, thiepines, diazepines, benzodiazepines, dioxepines, and dithiepines, are reviewed.

The review covers work published in the calendar year 2012. Novel reaction chemistry and new ring synthetic methods for azepines, benzoazepines, oxepines, thiepines, diazepines, benzodiazepines, dioxepines, and dithiepines are reviewed.

The review covers work published in the calendar year 2010. Novel reaction chemistry and new ring synthetic methods for azepines, benzoazepines, oxepines, thiepines, diazepines, benzodiazepines, dioxepines, dithiepines are reviewed.

This chapter reviews the chemistry of seven-membered heterocycles published in 2009 and presents the research focussing on the construction and reactions of these heterocyclic systems. In recent years, there appears to have been a trend toward more complex molecules with more than one heteroatom. Palladium-catalyzed intramolecular oxidative allylic C-H amination favor the formation of azepines. Intramolecular hydroamination with a zirconium complex gives cyclic amines including azepine and benzazepine derivatives in good yields. The gold-catalyzed cycliszation at the C-2 of indole onto a tethered alkyne occurrs preferentially to give the 8-endo-dig product, except when bulky phosphine ligands are used. While benzodiazepines and benzothiazepines continue to be important heterocyclic motifs in the synthesis of biologically active molecules, there has been resurgence in the synthesis of azepines and their fused derivatives. Reviews published on seven-membered heterocycles during 2009 included a summary of the strategies toward the synthesis of the stemona alkaloids that contain a pyrroloazepine system and the synthesis of 3-methylbenzoxepines and 3-methyl-1-benzoxepines.