Abstract
Analogs of the antimitotic herbicide oryzalin (3,5-dinitro-N4,N4-di-n-propylsulfanilamide) were recently prepared that were more potent in vitro than the parent compound against the kinetoplastid parasite Leishmania donovani (Bioorg Med Chem Lett 12:2395-2398, 2002). In the present work, we show that the most active molecule in the group, N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5), is a potent, selective antimitotic agent against kinetoplastid parasites. GB-II-5 possesses IC50 values of 0.41 and 0.73 μM in vitro against two strains of the related parasite Trypanosoma brucei but is much less toxic to J774 murine macrophages and PC3 prostate cancer cells, exhibiting IC50 values of 29 and 35 μM against these lines, respectively. Selectivity is also observed for GB-II-5 with purified leishmanial and mammalian tubulin. The assembly of 15 μM leishmanial tubulin is completely inhibited by 10 μM GB-II-5, whereas 40 μM GB-II-5 inhibits the assembly of 15 μM porcine brain tubulin by only 17%. In cultured L. donovani and T. brucei, treatment with 5 and 0.5 μM GB-II-5, respectively, causes a striking increase in the fraction of G2M cells compared with control. Given the potency and selectivity of this agent against kinetoplastid tubulin, GB-II-5 emerges as an exciting new antitrypanosomal and antileishmanial lead compound.
- Received May 30, 2003.
- Accepted September 3, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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