Selective Inhibition of Escherichia coli RNA and DNA Topoisomerase I by Hoechst 33258 Derived Mono- and Bisbenzimidazoles

Journal of Medicinal Chemistry
Nihar RanjanDev P Arya

Abstract

A series of Hoechst 33258 based mono- and bisbenzimidazoles have been synthesized and their Escherichia coli DNA topoisomerase I inhibition, binding to B-DNA duplex, and antibacterial activity has been evaluated. Bisbenzimidazoles with alkynyl side chains display excellent E. coli DNA topoisomerase I inhibition properties with IC50 values <5.0 μM. Several bisbenzimidazoles (3, 6, 7, 8) also inhibit RNA topoisomerase activity of E. coli DNA topoisomerase I. Bisbenzimidazoles inhibit bacterial growth much better than monobenzimidazoles for Gram-positive strains. The minimum inhibitory concentration (MIC) was much lower for Gram positive bacteria (Enterococcus spp. and Staphylococcus spp., including two MRSA strains 0.3-8 μg/mL) than for the majority of Gram negative bacteria (Pseudomonas aeruginosa, 16-32 μg/mL, Klebsiella pneumoniae > 32 μg/mL). Bisbenzimidazoles showed varied stabilization of B-DNA duplex (1.2-23.4 °C), and cytotoxicity studies show similar variation dependent upon the side chain length. Modeling studies suggest critical interactions between the inhibitor side chain and amino acids of the active site of DNA topoisomerase I.

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Citations

Sep 1, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Andrea BistrovićSilvana Raić-Malić
Jul 7, 2018·Beilstein Journal of Organic Chemistry·Sayantan BhaduriDev P Arya
May 1, 2019·Medicinal Chemistry·Smita VermaS J S Flora
Oct 4, 2019·Scientific Reports·Jordan ChamberlinDev P Arya
Jan 7, 2021·Microorganisms·Ahmed SeddekYuk-Ching Tse-Dinh
Jul 1, 2021·The Journal of Organic Chemistry·Shyamal Kanti BeraPrasenjit Mal

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