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 N1-phenyl-3,5-dinitro-N4,N4-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 IC50 values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4 μM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18 μM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3 μM), and in vitro toxicity against Vero cells (16 vs 9.7 μM). 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.

Analogues of antiparasitic antitubulin dinitroaniline sulfonamide 2b have been prepared. Dicyano compound 5 displays biological activity comparable to 2b.Figure optionsDownload as PowerPoint slide