Diosgenone synthesis, anti-malarial activity and QSAR of analogues of this natural product.

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.

• Authors: Adriana Pabón, Gustavo Escobar, Esteban Vargas, Víctor Cruz, Rafael Notario, Silvia Blair, Fernando Echeverri
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 18 Issue 3 Pg. 3356-78 (Mar 14 2013) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 23493102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antimalarials
• Spiro Compounds
• Triterpenes
• diosgenone
• 17-alpha-Hydroxyprogesterone

Topics

• 17-alpha-Hydroxyprogesterone (pharmacology)
• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cell Survival (drug effects)
• Drug Evaluation, Preclinical
• Drug Resistance
• Hep G2 Cells
• Humans
• Inhibitory Concentration 50
• Malaria (drug therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Parasitemia (drug therapy)
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Quantitative Structure-Activity Relationship
• Spiro Compounds (chemical synthesis, chemistry, pharmacology)
• Triterpenes (chemical synthesis, chemistry, pharmacology)