Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides

N1-Phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (1) and N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC50 values under 500 nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N1-(3-hydroxy)phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (21) displays an IC50 value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.

Seventeen new dinitroaniline sulfonamides and eleven dinitroaniline benzamides are reported. Nine of the sulfonamides display in vitro IC50 values under 500 nM against African trypanosomes.Figure optionsDownload as PowerPoint slide