A productive synthesis of benzo[a]phenoxazine derivative SSJ-183 (1), a promising lead for antimalarial agents, was developed using a one pot procedure. Furthermore, N-deethylated metabolite 3 and bis-N,N-deethylated metabolite 4 were synthesized by the application of the method. The metabolites 3 and 4 showed comparable and ∼2-fold increased activities against drug-sensitive and drug-resistant Plasmodium falciparum parasites.

01 Jul 2011·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Plasmodium berghei proteome changes in response to SSJ-183 treatment

Q3 · MEDICINE

Article

Author: Chika Arai ; Abu Bakar ; Jun Lu ; Masataka Ihara

The benzo[a]phenoxazine derivative, SSJ-183 has shown excellent anti-malarial efficacy and safety. However, its mechanism of action is unclear. We investigated the effect of SSJ-183 on the rodent malarial parasite, Plasmodium berghei. We analyzed changes in protein expression in the erythrocytic cycle of P. berghei with or without 18 h of SSJ-183 treatment by two-dimensional gel electrophoresis. We confirmed results with matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry. After treatment, seven main proteins were significantly down-regulated, and two were up-regulated; results were reproduced in three independent tests. Some of these proteins were hypothetical parasite proteins or unnamed host products. However, three proteins were identified as a heat shock protein, a disulfide isomerase precursor, and berghepain-2 from P. berghei. All three showed reduced expression after SSJ-183 treatment. This suggested that SSJ-183 was a good anti-malarial drug candidate because it targeted parasite chaperone proteins.

Drug Design, Development and TherapyQ3 · MEDICINE

In vitro and in vivo characterization of the antimalarial lead compound SSJ-183 in Plasmodium models

Q3 · MEDICINE

ArticleOA

Author: Isamu Itoh ; Christian Scheurer ; Pascal Fantauzzi ; David Shackleford ; Susan Ann Charman ; Karen Louise White ; Masataka Ihara ; Jeremy Burrows ; Ian C Bathurst ; Sarah Schleiferbock ; Julie Lotharius ; Sergio Wittlin ; Reto Brun ; Julia Morizzi

The objective of this work was to characterize the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activity profile of the recently discovered lead compound SSJ-183. The molecule showed in vitro a fast and strong inhibitory effect on growth of all P. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. Furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite strains. In vivo, SSJ-183 showed a rapid onset of action, comparable to that seen for the antimalarial drug artesunate. SSJ-183 exhibited a half-life of about 10 hours and no significant differences in absorption or exposure between noninfected and infected mice. SSJ-183 appears to be a promising new lead compound with an attractive antimalarial profile.

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Indication	Highest Phase	Country/Location	Organization	Date
Malaria, Falciparum	Discovery	Japan	Synstar Japan	-
Malaria, Falciparum	Discovery	Switzerland	MMV Medicines for Malaria Venture	-

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