Synthesis and Antitubulin Activity of N~1- and N~4-Substituted 3,5-Dinitro Sulfanilamides against African Trypanosomes and Leishmania

摘要

Thirty analogues of N~1-phenyl-3,5-dinitro-N~4,N~4-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N~1-phenyl-3,5-dinitro-N~4,N~4-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC50 values of 0.12 and 2.6 M against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC_(50) of 6.9 M and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N~1-aryl-3,5-dinitro-N~4,N~4-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.