Synthesis and evaluation of dinitroanilines for treatment of cryptosporidiosis.
The efficacy of a series of dinitroaniline herbicide derivatives for the treatment of Cryptosporidium parvum infections has been studied. The lead compounds oryzalin (compound 1) and trifluralin (compound 2) have low water solubility (<3 ppm) which was alleged to be a major contributor to their poor pharmacokinetic availability. Derivatives of compounds 1 and 2 were synthesized. In these derivatives the functionality at the C-1 amine position or the C-4 position was substituted with groups with various hydrophilicities to determine if a direct relation existed between water solubility and overall activity. The chlorinated precursors of these derivatives were also examined and were found to be less active in the C. parvum assays, a result in direct contrast to earlier work with Leishmania. Enhanced water solubility alone did not overcome the drug availability problem; however, several candidates with similar activities but with toxicities lower than those of the lead compounds were produced.
Benbow
J W
JW
Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, USA. jwb4@lehigh.edu
Bernberg
E L
EL
Korda
A
A
Mead
J R
JR
D000818:Animals; D002478:Cells, Cultured; D003049:Coccidiostats / Q000627:therapeutic use; D003457:Cryptosporidiosis / Q000188:drug therapy / Q000469:parasitology; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000254:growth & development; D004136:Dinitrobenzenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004285:Dogs; D013329:Structure-Activity Relationship; D013424:Sulfanilamides; D014274:Trifluralin / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000627:therapeutic use
D003049:Coccidiostats; D004136:Dinitrobenzenes; D013424:Sulfanilamides; C012465:oryzalin; D014274:Trifluralin