Pre-systemic metabolism prevents in vivo antikinetoplastid activity of N1,N4-substituted 3,5-dinitro sulfanilamide, GB-II-150.

We previously showed that N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (denoted GB-II-150) possesses selective antimicrotubule activity against Leishmania donovani and Trypanosoma brucei in vitro [Bhattacharya, G., Herman, J., Delfin, D., Salem, M.M., Barszcz, T., Mollet, M., Riccio, G., Brun, R., Werbovetz, K.A., 2004. Synthesis and antitubulin activity of N(1)- and N(4)-substituted 3,5-dinitro sulfanilamides against African trypanosomes and Leishmania. Journal of Medicinal Chemistry 47, 1823-1832]. When GB-II-150 was administered orally to male Sprague-Dawley rats, extensive first-pass metabolism of the compound was observed and the oral bioavailability was zero. GB-II-150 displayed a half-life of 170 min and a clearance of 31.5 mL/min/kg in rats when administered intravenously. In vitro metabolism studies indicated that less than 5% of GB-II-150 remained intact after a 60-min incubation with rat liver S9 fraction. As expected, the compound was extensively metabolized, with the major products resulting from N1-ring oxidation, N4-alkane oxidation, N4-oxidation, and nitro reduction. These data indicate that GB-II-150 undergoes rapid and extensive first-pass metabolism, precluding the attainment of effective systemic drug concentrations and explaining the lack of in vivo antitrypanosomal activity of this compound.

An improved procedure for the preparation of 8-substituted guanines.

The preparation of 8-substituted guanines using a new phosphorus(III)-mediated cyclisation of 4-acylamino-5-nitrosopyrimidines as the key step is described.

Synthesis, biological evaluation, and molecular modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as antikinetoplastid antimicrotubule agents.

Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. Analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC(50) values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4 microM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18 microM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3 microM), and in vitro toxicity against Vero cells (16 vs 9.7 microM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.

Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides.

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.