3 research outputs found
Identification of potent chromone embedded [1,2,3]-triazoles as novel antitubercular agents
Supplementary data of compounds including characterization, bioactivity and computational studies of compound
Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing
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 <i>Mycobacterium
tuberculosis</i> (<i>Mtb</i>) 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 <i>Mtb</i> strains harboring mutations
that confer resistance to aminopiperidines based NBTIs and <i>Mtb</i> 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
Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding
Structure–activity
relationship (SAR) exploration on the
left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement
in the selectivity against hERG cardiac channel binding with concomitant
potent antimycobacterial activity. Bulky polar substituents at the
C-7 position of the naphthyridone ring did not disturb its positioning
between two base pairs of DNA. Further optimization of the polar substituents
on the LHS of the naphthyridone ring led to potent antimycobacterial
activity (Mtb MIC = 0.06 μM) against <i>Mycobacterium tuberculosis</i> (Mtb). Additionally, this knowledge provided a robust SAR understanding
to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase
and retains its antimycobacterial activity against moxifloxacin-resistant
strains of Mtb. Finally, we demonstrate <i>in vivo</i> proof
of concept in an acute mouse model of TB following oral administration
of compound <b>19</b>