Development of Carprofen analogues with activity against Mycobacterium tuberculosis

• Carprofen analogues were designed and optimised for activity against Mycobacterium tuberculosis and non-tuberculous mycobacterial pathogens. • A structure–activity relationship (SAR)-driven approach enhanced potency, reduced eukaryotic cell-toxicity and selectivity • Three series of carbazole-based derivatives were evaluated in whole-cell phenotypic assays. • Lead compound showed enhanced bactericidal activity against M. tuberculosis H37Rv. • This study highlights SAR-guided bioorganic synthesis as a strategy for drug discovery against drug-resistant tuberculosis. Carprofen, a veterinary non-steroidal anti-inflammatory drug, has demonstrated bactericidal activity against Mycobacterium tuberculosis and the closely related model organism M. bovis BCG. Herein, we present the SAR-driven optimisation of three series of carbazole-based carprofen analogues for increased antimycobacterial potency and selectivity over the human monocyte-derived THP-1 cell line. An efficient synthetic route was employed to assemble a range of carprofen analogues which were then evaluated in whole-cell phenotypic assays to establish their activity against well-studied model organisms for M. tuberculosis . The most promising compound was further profiled against M. tuberculosis H37Rv, confirming the identification of a potent antitubercular carbazole with significantly enhanced therapeutic potential.