title: Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore.
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, compounds 41, 51 and 53 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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, United States.
authors.forename: Santosh B
authors.initials: SB
authors.lastname: Salunke
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, 460 W 12th Avenue, Columbus, OH 43210, United States; Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Wexner Medical Center, 460 W 12th Avenue, Columbus, OH 43210, United States.
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, United States; Division of Pharmaceutical and Organic Chemistry, M. & N. Virani Science College, Saurashtra University, Rajkot 360005, Gujarat, India.
authors.forename: Naval P
authors.initials: NP
authors.lastname: Kapuriya
authors.affiliation: Department of Pathology, The Ohio State University, 410 W. 10th Avenue, Columbus, OH 43210, United States.
authors.forename: Joan-Miquel
authors.initials: JM
authors.lastname: Balada-Llasat
authors.affiliation: Department of Pathology, The Ohio State University, 410 W. 10th Avenue, Columbus, OH 43210, United States.
authors.forename: Preeti
authors.initials: P
authors.lastname: Pancholi
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, 460 W 12th Avenue, Columbus, OH 43210, United States; Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Wexner Medical Center, 460 W 12th Avenue, Columbus, OH 43210, United States. Electronic address: larry.schlesinger@osumc.edu.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, United States; Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Electronic address: chen.844@osu.edu.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000068579:Celecoxib / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D000068579:Celecoxib
keywords: Antimicrobial agents; Celecoxib; Drug repurposing; Multi-drug-resistant tuberculosis; Tuberculosis