Structure‐Guided Discovery of Antitubercular Agents That Target the Gyrase ATPase Domain

In this study we explored the pharmaceutically underexploited ATPase domain of DNA gyrase (GyrB) as a potential platform for developing novel agents that target Mycobacterium tuberculosis . In this effort a combination of ligand‐ and structure‐based pharmacophore modeling was used to identify structurally diverse small‐molecule inhibitors of the mycobacterial GyrB domain based on the crystal structure of the enzyme with a pyrrolamide inhibitor (PDB ID: 4BAE). Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 5 [( E )‐5‐(5‐(2‐(1 H ‐benzo[ d ]imidazol‐2‐yl)‐2‐cyanovinyl)furan‐2‐yl)isophthalic acid; IC 50 =4.6±0.1 μ m ], which was subsequently tailored through a combination of molecular modeling and synthetic chemistry to yield the optimized lead compound 24 [( E )‐3‐(5‐(2‐cyano‐2‐(5‐methyl‐1 H ‐benzo[ d ]imidazol‐2‐yl)vinyl)thiophen‐2‐yl)benzoic acid; IC 50 =0.3±0.2 μ m ], which was found to display considerable in vitro efficacy against the purified GyrB enzyme and potency against the H 37 Rv strain of M. tuberculosis . Structural handles were also identified that will provide a suitable foundation for further optimization of these potent analogues.