Background: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis.
As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths
in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR &
XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly
promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug
resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and
is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines
have been reported with their antitubercular and ATP synthase inhibitory activity.
Methods: To understand the role of physicochemical parameters like hydrophobicity, electronic and
steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR)
studies have been carried out using the computed parameters as independent variable and activity (-log
IC50/MIC) as the dependent variable.
Results: The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and
negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters
have high predictivity as also shown on external data set and the mean value of the computed 3D parameters
of enantiomers may be used in QSAR analysis for racemic compounds.
Conclusion: These results are also substantiated by pharmacophore modeling. The similar dependence
of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as
the main target for antitubercular activity and the QSAR models may be useful in the identification of
novel antitubercular agents.