Cycloaddition of the (fluoroalkyl)imines 7a-c with the ketene formed in situ from (benzyloxy)acetyl chloride and triethylamine provided stereoselectively cis-(fluoroalkyl)azetidinones 5a-c in moderate yields. The corresponding N-Boc-isoserinates 11a-c and protected synthons 12a-c have been prepared from these azetidinones 5a-c. Cycloaddition of the chiral imine 18 (R F ) CF 3 ) with the same ketene led to the diastereoisomeric azetidinones 19 and 20 with a poor diastereoisomeric excess (10-20%). However, the two diastereoisomers could be easily separated by crystallization and provided enantiomerically pure N-Boc-isoserinates 23 (R,R) and 23 (S,S) after ring opening and debenzylation.
Fluoroalkyl ethers (4) of dihydroartemisinin (2) have been prepared by reaction of fluoroalkyl alcohols with dihydroartemisinin by different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers 4a-d derived from primary fluoroalkyl alcohols were obtained in moderate to good yields by these methods. Ethers 4e-j have been prepared from fluoroalkyl secondary and tertiary alcohols and phenol using the Mitsunobu reaction. Although in vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate, in vivo activities against Plasmodium berghei (NT 173) are excellent.
The antimalarial activity of 10 alpha-trifluoromethylhydroartemisinin (TFMHA) was compared to that of dihydroartemisinin (DHA) in the Plamodium berghei mouse model. Treatment with TFMHA in mice infected with a P. berghei chloroquine-sensitive strain at 25 mg/kg for 3, 5, and 7 d, or DHA at the same dose for 7 d showed the parasite was eliminated from the host within 2.6 d. The radical cure and survival rates of these mice up to 60 d after infection were 90-100%. In mice infected with the P. berghei chloroquine-resistant strain, TFMHA used at 25 mg/kg/day for 3, 5, or 7 d reduced parasitaemia within 2 d. The radical cure and survival rates of these animals up to 60 d after infection were 30, 60, and 90% for the 3 treatment durations respectively. In contrast, DHA only had an inhibitory effect on the growth of the parasite within the first few days of treatment and could not eliminate the parasite even after 7 d of treatment. There was a 100% relapse and all mice died within 28 d after infection. The acute toxicity of TFMHA as determined by the median lethal dose (LD50) in mice treated orally was 820 mg/kg. In rabbits, TFMHA given orally at 20 mg/kg once daily for 28 successive days had no effect on the bodyweight, haematological, biochemical, histopathological and electrocardiogram parameters. The results showed that TFMHA is an effective antimalarial drug with a low level of toxicity.
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