Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles

Hoechst dyes are well known DNA binders that non-selectively inhibit the function of mammalian topoisomerase I and II. Herein, we show that Hoechst 33258 based bisbenzimidazoles (DPA 151-154), containing a terminal alkyne, are effective and selective inhibitors of E. coli topoisomerase I. These bisbenzimidazoles displayed topoisomerase I inhibition much better than Hoechst 33342 or Hoechst 33258 with IC50 values in the range of 2.47-6.63 mu M. Bisbenzimidazoles DPA 151-154 also display selective inhibition of E. coli topoisomerase I over DNA gyrase and human topoisomerases I and II, and effectively inhibit bacterial growth.