Ana Maria Faísca Phillips

Synthesis and biological evaluation of α-hydroxyalkylphosphonates as new antimicrobial agents

A set of α-quaternary 3-chloro-1-hydroxyalkylphosphonates, analogues of fosfomycin and fosfonochlorin, some of which are new compounds, was synthesized. The compounds were screened for bioactivity against several clinical and standard microbial isolates. Some were found to have moderate activity. The activity was higher with phenyl protection of the phosphoryl ester groups and α-phenyl substitution. Compound 11 was as effective or more potent than fosfomycin or chloramphenicol against several Gram-negative bacteria as well as against some Gram-positive ones.

Synthesis of new chiral amines with a cyclic 1,2-diacetal skeleton derived from (2R, 3R)-(+)-tartaric acid.

The syntheses of new chiral cyclic 1,2-diacetals from (2R, 3R)-( )-tartaric acid are described. C(2)-symmetrical diamines were prepared via direct amidation of the tartrate or from the corresponding bismesylate via reaction with sodium azide. For C1-symmetrical compounds, the Appel reaction was used to form the key intermediate, a monochlorocarbinol, from the diol. Some of the new chiral compounds, produced in good to high yields, may be potentially useful as asymmetric organocatalysts or as nitrogen and sulfur chelating ligands for asymmetric metal catalyzed reactions. Thus, a bis-N-methyl-methanamine derivative, used in substoichiometric amounts, was found to catalyze the enantioselective addition of cyclohexanone to (E)-beta-nitrostyrene with high diastereoselectivity (syn / anti = 92:8), albeit giving moderate optical purity (syn: 30 %).

Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.

The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells.