Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing

Abstract

Type II topoisomerases are well conserved across the bacterial species, and inhibition of DNA gyrase by fluoroquinolones has provided an attractive option for treatment of tuberculosis (TB). However, the emergence of fluoroquinolone-resistant strains of Mycobacterium tuberculosis (Mtb) poses a threat for its sustainability. A scaffold hopping approach using the binding mode of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification of a novel class of benzimidazoles as DNA gyrase inhibitors with potent anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal structure suggested that this class of compound makes key contacts in the enzyme active site similar to the reported NBTIs. This observation was further confirmed through the measurement of DNA gyrase inhibition, and activity against Mtb strains harboring mutations that confer resistance to aminopiperidines based NBTIs and Mtb strains resistant to moxifloxacin. Structure-activity relationship modification at the C-7 position of the left-hand side ring provided further avenue to improve hERG selectivity for this chemical series that has been the major challenges for NBTIs.

Solvent‐Free Oxidative Synthesis of 2‐Substituted Benzimidazoles by Immobilized Cobalt Oxide Nanoparticles on Alumina/Silica Support

“…Nitrogen containing heterocyclic compounds are pivotal building blocks in natural products, pharmaceuticals and organic/polymeric materials . In particular, benzimidazoles are medicinally important bioactive heterocyclic scaffolds and found to have a broad spectrum of biological and pharmacological properties including anti‐bacterial, anti‐fungal, anti‐inflammatory, anti‐ulcer, anti‐cancer, and anti‐HIV activities . Owing to the parmaceutical importance, various methods have been reported for their synthesis.…”

Identification of Phenoxyalkylbenzimidazoles with Antitubercular Activity

“…The benzimidazole scaffold has also shown anti-mycobacterial activity in vitro [9][10][11][12][13][14] . Ojima et al 15 tuberculosis.…”

Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

“…[8][9][10]16 The synthesis of compounds with bulky substitutions (2−9) are illustrated in Scheme 1. Nucleophilic displacement of halo substituted naphthyridones (I) with corresponding carbinol (II) using cesium carbonate under thermal heating condition resulted in title compounds 2−19.…”

“…This design was based on the initial SAR observations made during the lead optimization of NBTIs as novel antimycobacterial agents reported earlier. 16 However, we have not explored similar substitution at C-6 position as the SAR studies suggest that a compound with 6-methoxy substitution was found to be inactive against Mtb. 8 We hypothesized that by lowering the logD and modulation of polarity via bulky polar substitutions on LHS ring may provide structural diversity to mitigate hERG liability.…”

“…Thus, the large polar bulky substitution at the C-7 position does not change the potency and hERG selectivity among the compounds reported in Table 2 A homology model based on the binding mode of aminopiperidine based NBTIs to Mtb GyrA has been reported. 8,16 In order to understand the effect of bulky polar substitutions on NBTIs binding to Mtb GyrA subunit, we docked compounds 2 and 3. The possible binding modes of compounds 2 and 3 in the Mtb GyrA homology model are depicted in Figure 2.…”