n1-phenyl-3-5-dinitro-n4-n4-di-n-propylsulfanilamide and oryzalin

The synthesis and evaluation of 20 dinitroanilines and related compounds against the obligate intracellular parasite Toxoplasma gondii is reported. Using in vitro cultures of parasites in human fibroblasts, we determined that most of these compounds selectively disrupted Toxoplasma microtubules, and several displayed sub-micromolar potency against the parasite. The most potent compound was N(1),N(1)-dipropyl-2,6-dinitro-4-(trifluoromethyl)-1,3-benzenediamine (18b), which displayed an IC(50) value of 36 nM against intracellular T. gondii. Based on these data and another recent report [Ma, C.; Tran, J.; Gu, F.; Ochoa, R.; Li, C.; Sept, D.; Werbovetz, K.; Morrissette, N. Antimicrob. Agents Chemother. 2010, 54, 1453], an antimitotic structure-activity relationship for dinitroanilines versus Toxoplasma is presented.

Topics: Animals; Dinitrobenzenes; Drug Evaluation, Preclinical; Fibroblasts; Humans; Magnetic Resonance Spectroscopy; Structure-Activity Relationship; Sulfanilamides; Toxoplasma

Despite years of use as commercial herbicides, it is still unclear how dinitroanilines interact with tubulin, how they cause microtubule disassembly, and why they are selectively active against plant and protozoan tubulin. In this work, through a series of computational studies, a common binding site of oryzalin, trifluralin, and GB-II-5 on apicomplexan and kinetoplastid alpha-tubulin is proposed. Furthermore, to investigate how dinitroanilines affect tubulin dynamics, molecular dynamics simulations of Leishmania alpha-tubulin with and without a bound dinitroaniline are performed. The results obtained provide insight into the molecular mechanism by which these compounds interact with tubulin and function to prevent microtubule assembly. Finally, to aid in the design of effective parasitic microtubule inhibitors, several novel dinitroaniline analogues are evaluated. The location of the binding site and the relative binding affinities of the dinitroanilines all agree well with experimental data.

Topics: Aniline Compounds; Animals; Apicomplexa; Binding Sites; Binding, Competitive; Dinitrobenzenes; Kinetoplastida; Molecular Structure; Protein Conformation; Protein Structure, Tertiary; Structure-Activity Relationship; Sulfanilamides; Trifluralin; Tubulin

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 microM 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 microM against these lines, respectively. Selectivity is also observed for GB-II-5 with purified leishmanial and mammalian tubulin. The assembly of 15 microM leishmanial tubulin is completely inhibited by 10 microM GB-II-5, whereas 40 microM GB-II-5 inhibits the assembly of 15 microM porcine brain tubulin by only 17%. In cultured L. donovani and T. brucei, treatment with 5 and 0.5 microM 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.

Topics: Animals; Antiprotozoal Agents; Dinitrobenzenes; Growth Inhibitors; Herbicides; Kinetoplastida; Leishmania donovani; Microtubules; Rats; Sulfanilamides; Swine; Trypanosoma brucei brucei

Novel dinitroaniline sulfonamides based on the herbicide oryzalin 3 were synthesized and evaluated for activity against the parasitic protozoan Leishmania donovani and against leishmanial tubulin, the putative antiparasitic target of oryzalin. A subset of these compounds possess more activity against both Leishmania and the target protein in vitro. Compound 20 displays improved potency against leishmanial tubulin and is 13.4-fold more active against L. donovani axenic amastigotes than oryzalin.

Topics: Animals; Antiprotozoal Agents; Dinitrobenzenes; Inhibitory Concentration 50; Leishmania donovani; Structure-Activity Relationship; Sulfanilamides; Sulfanilic Acids; Sulfonamides; Tubulin