In vitro assessment of the pharmacodynamic properties and the partitioning of OZ277/RBx-11160 in cultures of Plasmodium falciparum

Objectives: Using synchronous cultures of Plasmodium falciparum malaria, the stage sensitivity of the parasite to OZ277 (RBx-11160), the first fully synthetic antimalarial peroxide that has entered Phase II clinical trials, was investigated in vitro over a concentration range of 1× to 100× the IC50. Secondly, partitioning of OZ277 into P. falciparum-infected red blood cells (RBCs) and uninfected RBCs was studied in vitro by measuring its distribution between RBCs and plasma (R/P). Methods: The effects of timed in vitro exposure (1, 6, 12 or 24 h) to OZ277 were monitored by incorporation of [3H]hypoxanthine into parasite nucleic acids and by light-microscopic analysis of parasite morphology. Partitioning studies were performed with radiolabelled [14C]OZ277. Results: After 1 h of exposure to OZ277 at the highest concentration (100× the IC50) followed by removal of the compound, the hypoxanthine assay showed that growth of mature stages of P. falciparum was reduced to below 20%. Young ring forms were slightly less sensitive (43% growth). Similar stage-specific profiles were found for the antimalarial reference compounds artemether and chloroquine. Strong inhibition (≤6% growth) of all parasite stages was observed when the parasites were exposed to each of the three compounds for 6 h or longer. After removal of the compounds, the parasites did not recover, indicating that the observed growth inhibitions were cytotoxic rather than cytostatic. Pyrimethamine was confirmed to be active exclusively against young schizonts. Light-microscopic analysis also demonstrated the specificity of pyrimethamine against the schizont forms and showed that OZ277, artemether and chloroquine attenuated parasite growth more rapidly than did pyrimethamine. The R/P for OZ277 was 1.5 for uninfected RBCs and up to 270 for infected RBCs. Conclusions: The present study indicates similar stage-specific profiles for OZ277 and for the more well-established antimalarial agents artemether and chloroquine. Secondly, the study describes a significant accumulation of radiolabelled OZ277 in P. falciparum-infected RBC

Bisquinolines. 2. Antimalarial N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines

N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1−11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1−11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1−10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5−20 μM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series

Weak Base Dispiro-1,2,4-Trioxolanes: Potent Antimalarial Ozonides

Thirty weak base 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. Amino amide trioxolanes had the best combination of antimalarial and biopharmaceutical properties. Guanidine, aminoxy, and amino acid trioxolanes had poor antimalarial activity. Lipophilic trioxolanes were less stable metabolically than their more polar counterparts

Studies on Plasmepsins I and II from the Malarial Parasite Plasmodium falciparum and their exploitation as drug targets

Malaria is one of the major diseases of the world. Between 2 to 3 million deaths occur each year, mainly children under 5 years of age living in sub-Saharan Africa. Up to 300 million people are infected at any given time and up to 2 billion people (close to half the world population) live in malarious areas and are at risk of infection. The most virulent of the four malaria species which infect humans is Plasmodium falciparum and the spread of resistance by this species to the available drugs, such as chloroquine, has resulted in a critical world health situation with a desperate need to develop new drugs