Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Salunke, Santosh B.; Azad, Abul K.; Kapuriya, Naval P.; Balada-Llasat, Joan-Miquel; Pancholi, Preeti; Schlesinger, Larry S.; Chen, Ching-Shih
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 9(2015)
• Page Start: 1935
• Page End: 1943
• Publication Date: 2015-05-01
• Subjects: M.tb Mycobacterium tuberculosis -- TB tuberculosis -- INH isoniazid -- IC50 50% inhibitory concentration -- CFU colony forming unit -- MIC minimum inhibitory concentration -- MDR multi drug-resistant -- XDR extremely drug-resistant -- TDR totally drug-resistant -- PDK-1 phosphoinositide-dependent kinase-1 -- ATP adenosine triphosphate -- WHO World Health Organization; Tuberculosis -- Celecoxib -- Antimicrobial agents -- Multi-drug-resistant tuberculosis -- Drug repurposing; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.041
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The identification of compounds with anti-mycobacterial activity within classes of molecules that have been developed for other purposes is a fruitful approach for the development of anti-tuberculosis (TB) agents. In this study we used the scaffold of celecoxib which exhibits several activities against different pathogens, for the design and focused synthesis of a library of 64 compounds. For the primary screen, we used a bioluminescence-based method by constructing a luciferase-expressing reporter M.tb strain which contains the entire bacterial Lux operon cloned in a mycobacterial integrative expression vector. Through the screening of this library, we identified 6 hit compounds with high in vitro anti-mycobacterial activity (IC50 ∼0.18–0.48 μM). In particular, compounds41, 51 and53 were capable of inhibiting M.tb as effectively as the anti-TB drug isoniazid (INH) at 5 μM over a 72-h period, as analyzed by both bioluminescence- and colony forming unit (CFU)-based assays. All hit compounds also showed anti- M.tb activities against several multi-drug-resistant (MDR) strains. Most of the hit compounds showed no cytotoxicity for human macrophages at concentrations as high as 40 μM, setting the stage for further optimization and development of these anti-TB hit compounds both ex vivo and in vivo.