Bioguided antiplasmodial isolation of six new labdane-type diterpenoids from the stem bark of Croton sylvaticus Hochst. Ex. Krauss.

The CH 2 Cl 2 -MeOH (1:1, v/v) extract of Croton sylvaticus stem bark selectively exhibited good antiplasmodial activity during preliminary screening against the multidrug-resistant (Dd2) and chloroquine sensitive (3D7) strains of Plasmodium falciparum with IC 50 values of 10.57 and 18.47 μg/mL, respectively. After fractionation, the fractions exhibited moderate to good activity with IC 50 values ranging from 4.31 to 25.49 μg/mL. The purification of these fractions led to the isolation of six new labdane-type diterpenoids named sylvacrotonins A F (1 6), alongside seven known compounds (7 13). Their structures were determined based on the analysis of their NMR and MS data. The isolated compounds were assessed in vitro for their antiplasmodial activity against Pf 3D7 and Pf Dd2. The new labdane-type diterpenoids showed moderate antiplasmodial activity against the two P. falciparum strains, with compound 6 being the most active, with IC 50 values of 11.26 and 21.80 μg/mL against Pf Dd2 and Pf 3D7, respectively. Cytotoxic assays were performed on African green monkey kidney Vero cells to ensure that the obtained activity was specific to the parasites. Interestingly, all the tested extracts, fractions, and isolated compounds showed acceptable selectivity (SI > 10) against both Plasmodium strains, except fractions CSB-E (SI = 3.93) and CSB-C (SI = 9.22) against Pf 3D7. Globally, with resistance indexes (RIs) lower than 1, all the tested samples were found to be more active against multidrug-resistant (Pf Dd2) than sensitive (Pf 3D7) strains. Furthermore, all the isolated compounds exhibited cell cytotoxicity in the normal Vero cell line. The results from this study confirm the use of C. sylvaticus in malaria - endemic countries for its management and suggest that further lead-optimization studies on hit compounds could drive to the identification of potential lead molecules for antimalarial control and eradication. [Display omitted] ▪ An extract of Croton sylvaticus stem bark exhibited appreciable antiplasmodial activity. ▪ Bioguided investigation of fractions led to the isolation of twelve compounds. ▪ Six previously undescribed diterpenoids, sylvaticrotonins A-F, were isolated. ▪ Sylvaticrotonin F [6 β -hydroxynidorellol (6)] was the most active compound with IC 50 values of 11.26 and 21.80 μg/mL. ▪ Their structures were determined based on the analysis of their NMR and MS data. [ABSTRACT FROM AUTHOR]