Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles

Abstract

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 μM. 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.

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents

“…31 Hoechst 33258-based bisbenzimidazoles containing terminal alkyne displayed selective inhibition of E. coli topoisomerase I over human topoisomerase I and II, and effectively inhibited bacterial growth. 32 Hoechst 33258 was shown to bind fungal nucleic acid and can potentially be used against pneumocystis and possibly other fungi. 33 These studies piqued our curiosity, and we decided to further synthesize and explore novel benzimidazole derivatives in a structure-activity-relationship study for their antifungal properties.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Systems Medicine Approach to NRF2 in Chronic Diseases Five families of PPI inhibitors have been described: tetrahydroisoquinoline (Jnoff et al, 2014;Richardson et al, 2015), thiopyrimidine (Marcotte et al, 2013), naphthalene (Jiang et al, 2014b), carbazone (Ranjan et al, 2014), and urea derivatives (Sato et al, 2013). Table 3 compiles recent patents addressing these small molecules.…”

Targeting Bacterial Topoisomerase I to Meet the Challenge of Finding New Antibiotics

“…New bisbenzimidazole analogues of these Hoechst dyes that can selectively target bacterial DNA topoisomerase I over human topoisomerases have been synthesized and characterized [70–73]. 3,4-Dimethoxyphenyl bisbenzimidazole [70,71] (DMA, Compound 5 in Figure 3) as well as DPA 153 [72] with a terminal alkyne substitution (Compound 6 in Figure 3) represent independently discovered bisbenzimidazole analogues that inhibit E. coli topoisomerase I much more strongly than E. coli DNA gyrase, human topoisomerase I and human topoisomerase IIα. The IC 50 for E. coli topoisomerase I inhibition by DMA was found to be 3.8 μM [70], very similar to the IC 50 value of 2.5 μM for DPA 153 [72].…”

“…3,4-Dimethoxyphenyl bisbenzimidazole [70,71] (DMA, Compound 5 in Figure 3) as well as DPA 153 [72] with a terminal alkyne substitution (Compound 6 in Figure 3) represent independently discovered bisbenzimidazole analogues that inhibit E. coli topoisomerase I much more strongly than E. coli DNA gyrase, human topoisomerase I and human topoisomerase IIα. The IC 50 for E. coli topoisomerase I inhibition by DMA was found to be 3.8 μM [70], very similar to the IC 50 value of 2.5 μM for DPA 153 [72]. There was evidence that DMA can act as a poison inhibitor for E. coli topoisomerase I, increasing the level of DNA cleavage products [70].…”