ABSTRACT
Seven diterpenoids including four clerodane and three labdane derivatives, (13S)-ent-7beta-hydroxy-3-cleroden-15-oic acid (1), ent-7beta-hydroxy-2-oxo-3-cleroden-15-oic acid (2), ent-2,7-dioxo-3-clero-den-15-oic acid (3), ent-18-(E)-caffeoyloxy-7beta-hydroxy-3-cleroden-15-oic acid (4) (13S)-ent-18-(E)-coumaroyloxy-8(17)-labden-15-oic acid (5), ent-18-(E)-caffeoyloxy-8(17)-labden-15-oic acid (6), ent-15-(E)-caffeoyloxy-8(17)-labden-18-oic acid (7), have been isolated from an ethyl acetate extract of the leaves of Nuxia sphaerocephala, together with 17 known compounds. 3-Oxolup-20(29)-en-30-al (3-oxolupenal) (8) and 3beta-hydroxylup-20(29)-en-30-al (3beta-hydroxy-lupenal) (9) showed the best inhibitory activity against Plasmodium falciparum with the IC(50) values between 1.55 and 4.67 microg/ml in vitro, respectively. The structure and the relative stereochemistry of the compounds were established on the basis of their spectroscopic properties. The absolute configuration at C-13 of 1 and 5 was determined by the PGME amide procedure.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Diterpenes, Clerodane/chemistry , Diterpenes/chemistry , Plant Extracts/chemistry , Animals , Diterpenes/isolation & purification , Diterpenes/pharmacology , Diterpenes, Clerodane/isolation & purification , Diterpenes, Clerodane/pharmacology , Molecular Structure , Parasitic Sensitivity Tests , Plant Extracts/pharmacology , Plasmodium falciparum/drug effectsABSTRACT
A series of 'retinoid-like chalcones' and diverse derivatives relative to licochalcone A were synthesized from a new enaminone synthon. These syntheses occurred via a new aromatic annelation. These new derivatives have been tested in vitro as potential antimalarial agents. The 4-hydroxy-chalcone-like (compound 6a, derived from beta-ionone) exhibits a good and reproducible inhibitory effect on the in vitro culture of Plasmodium falciparum, with an IC 50 lower than 10 microM for inhibition of 3H-hypoxanthine uptake by parasites (respectively, 4.93 and 8.47 microM for strains K1 and Thaï).
Subject(s)
Antimalarials/chemical synthesis , Chalcone/chemical synthesis , Erythrocytes/parasitology , Plasmodium falciparum/drug effects , Retinoids/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Chalcone/analogs & derivatives , Chalcone/pharmacology , Humans , Inhibitory Concentration 50 , Malaria/blood , Malaria/drug therapy , Malaria/parasitology , Parasitemia/drug therapy , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Retinoids/chemistry , Retinoids/pharmacologyABSTRACT
BACKGROUND: Plasmodium falciparum outbreaks can occur in the coastal area of French Guiana, where the population is essentially non-immune. Two sporadic outbreaks were observed, including one with severe malaria cases. To characterize these outbreaks and verify previous observations of specific genotype characteristics in severe malaria in this area, all cases from each outbreak were studied. METHODS: P. falciparum genotypes for six genetic loci were determined by PCR amplification from peripheral blood parasites. The msp1/block2 and msp2 genotypes were determined by DNA sequencing. Microsatellite and varD genotyping was based on size polymorphism and locus-specific amplification. RESULTS: The outbreak including severe malaria cases was associated with a single genotype. The other mild malaria outbreak was due to at least five distinct genotypes. CONCLUSION: Two distinct types of outbreak occurred despite systematic and sustained deployment of malaria control measures, indicating a need for reinforced vigilance. The varD/B-K1 msp1 linkage and its association with severe malaria in this area was confirmed.