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Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2006 Aug 15; Vol. 14 (16), pp. 5699-710. Date of Electronic Publication: 2006 May 03. - Publication Year :
- 2006
-
Abstract
- N(1)-Phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (1) and N(1)-phenyl-3,5-dinitro-N(4),N(4)-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 IC(50) 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, N(1)-(3-hydroxy)phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (21) displays an IC(50) value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.
- Subjects :
- Animals
Antimitotic Agents chemical synthesis
Antiprotozoal Agents chemical synthesis
Benzamides chemical synthesis
Inhibitory Concentration 50
Liver metabolism
Rats
Structure-Activity Relationship
Sulfanilamides chemical synthesis
Tubulin metabolism
Antimitotic Agents pharmacology
Antiprotozoal Agents pharmacology
Benzamides pharmacology
Kinetoplastida drug effects
Leishmania donovani drug effects
Sulfanilamides pharmacology
Trypanosoma drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 14
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16675220
- Full Text :
- https://doi.org/10.1016/j.bmc.2006.04.017