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.

Figure 1

Structure of diosgenin and diosgenone, SN-1 and SN-2 S. nudum sapogenin.

Scheme 1

Diosgenone (2) and derivatives 7–15 prepared by modifications made in the A- and B-rings and the spiroketal system.

Scheme 2

Diosgenin derivatives 16–20 obtained by modifications made to the A- and B-rings. Diosgenin (1).

Scheme 3

SN-1 derivatives 21–24 produced by modifications made to the side chain and A-ring. SN-1 (3).

Figure 2

Percentage parasitemia inhibition in P. berghei-infected mice following treatment with derivatives 14 and 18.

Figure 3

Electrostatic and steric contours mapped onto compound 15.