Abstract
Solanum nudum Dunal steroids have been reported as being antimalarial compounds; however, their concentration in plants is low, meaning that the species could be threatened by over-harvesting for this purpose. Swern oxidation was used for hemisynthesis of diosgenone (one of the most active steroidal sapogenin diosgenin compounds). Eighteen structural analogues were prepared; three of them were found to be more active than diosgenone (IC50 27.9 μM vs. 10.1 μM, 2.9 μM and 11.3 μM). The presence of a 4-en-3-one grouping in the A-ring of the compounds seems to be indispensable for antiplasmodial activity; progesterone (having the same functional group in the steroid A-ring) has also displayed antiplasmodial activity. Quantitative correlations between molecular structure and bioactivity were thus explored in diosgenone and several derivatives using well-established 3D-QSAR techniques. The models showed that combining electrostatic (70%) and steric (30%) fields can explain most variance regarding compound activity. Malarial parasitemia in mice became reduced by oral administration of two diosgenone derivatives.
Highlights
Malaria is a parasitic disease which is responsible for about one million deaths annually [1]; its high morbidity and mortality affects more than 106 countries, in which there were nearly 216 million episodes of malaria in 2010 alone
This type of reaction has been reported for other compounds and resembles the primary transformation of steroidal sapogenins into progesterone [17]
A few reports concerning steroids’ antiplasmodial activity could be found in the pertinent literature, despite the fact some steroidal alkaloids having been shown to be active against malaria
Summary
Malaria is a parasitic disease which is responsible for about one million deaths annually [1]; its high morbidity and mortality affects more than 106 countries, in which there were nearly 216 million episodes of malaria in 2010 alone. There is a compelling need to look for new strategies for treating malaria [2] considering the above and first-line drugs’ high failure rates (i.e., chloroquine, amodiaquine, sulfadoxine/pyrimethamine) [3]; compounds having new mechanisms of action and less (or no) adverse effects are urgently needed. It is well-recognized that natural products represent a source of new drugs and several properties, including flavonoids, alkaloids (i.e., quinine), coumarins, quinines, terpenes and lactones (i.e., artemisinins) [4]. Diosgenone is only present in the plant in terms of a few milligrams per kilogram of plant material; obtaining it by hemisynthesis from commercial diosgenin was deemed reasonably logical and would lead to obtaining a further series of derivatives
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