Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors

• We report a new class of small molecule inhibitor of Mycobacterium tuberculosis gyrase ATPase domain.
• A structure based medium throughput virtual screening identified an initial hit compound 1.
• Hit expansion, leads compound 29 as potent GyrB inhibitory IC50 of 2.5 ± 0.1 μM.
• The molecules exhibited promising in-vitro MTB potency.
• The binding affinity of the inhibitor towards the GyrB domain was re-ascertained by DSF.

A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization.

A structure based medium throughput virtual screening of in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Initial hit is further optimized to study SAR and biological evaluation.Figure optionsDownload as PowerPoint slide