title: 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.affiliation: Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, 050010 Medellín, Colombia. apabon72@gmail.com
authors.forename: Adriana
authors.initials: A
authors.lastname: Pabón
authors.forename: Gustavo
authors.initials: G
authors.lastname: Escobar
authors.forename: Esteban
authors.initials: E
authors.lastname: Vargas
authors.forename: Víctor
authors.initials: V
authors.lastname: Cruz
authors.forename: Rafael
authors.initials: R
authors.lastname: Notario
authors.forename: Silvia
authors.initials: S
authors.lastname: Blair
authors.forename: Fernando
authors.initials: F
authors.lastname: Echeverri
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D013141:Spiro Compounds; D014315:Triterpenes; C469690:diosgenone; D019326:17-alpha-Hydroxyprogesterone