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Abstract
Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds.
Highlights
Malaria remains the most devastating tropical disease, with staggering infection and mortality statistics
With artemisinin as an illustrative example (Figure 1) [9,10,11,12], the identification of promising compounds in this way usually triggers medicinal chemistry efforts geared towards the total synthesis of the identified compounds and/or the generation of analogs, and which are aimed at providing a supplementary source of the product for further study, revealing structure-activity relationships (SAR), identifying more potent analogs and/or overcoming challenging physicochemical and biological properties
Natural products may be lead compounds in themselves, or more likely may serve as hits that may be useful in providing pharmacophores/templates that can guide the design of potentially superior analogs and/or the mining of existing databases of synthetic and semi-synthetic compounds for previously untested and potentially active analogs
Summary
Malaria remains the most devastating tropical disease, with staggering infection and mortality statistics. Metabolism and metabolite identification studies In silico (computational) and in vitro metabolism studies are primarily aimed at assessing the metabolic stability of promising hit and lead compounds, and are usually geared at providing useful information to guide and/or help in the interpretation of the results from subsequent pharmacokinetic studies and in vivo assays Such information enables the drug discovery scientists to design and synthesize analogs of the primary compound(s) that are potentially more stable to metabolism and are likely to have improved oral bioavailability profiles [25]. Natural product-derived pharmacophores and template-based virtual screening Upon the elucidation of the structure of a novel antimalarial compound from natural sources, and possibly informed by preliminary SAR data, it may be possible to identify its basic pharmacophoric unit(s) This facilitates more elaborate SAR studies, and allows for the systematic searches of databases and libraries of known compounds (from both natural and synthetic sources) for structural analogs. It has even been proposed that screening libraries should be intentionally optimized by adding to them molecules with biogenic or natural-product-like scaffolds [56], further underlining the value of natural products to such strategies
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