title: Synthesis of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazines that have antibacterial activity and also inhibit inorganic pyrophosphatase.
abstract: Inorganic pyrophosphatases are potential targets for the development of novel antibacterial agents. A pyrophosphatase-coupled high-throughput screening assay intended to detect o-succinyl benzoic acid coenzyme A (OSB CoA) synthetase inhibitors led to the unexpected discovery of a new series of novel inorganic pyrophosphatase inhibitors. Lead optimization studies resulted in a series of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine derivatives that were prepared by an efficient synthetic pathway. One of the tetracyclic triazine analogues 22h displayed promising antibiotic activity against a wide variety of drug-resistant Staphylococcus aureus strains, as well as activity versus Mycobacterium tuberculosis and Bacillus anthracis, at a concentration that was not cytotoxic to mammalian cells.
authors: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors: Wei
authors: W
authors: Lv
authors: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors: Biplab
authors: B
authors: Banerjee
authors: Department of Biological Sciences and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors: Katrina L
authors: KL
authors: Molland
authors: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, United States.
authors: Mohamed N
authors: MN
authors: Seleem
authors: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, United States.
authors: Adil
authors: A
authors: Ghafoor
authors: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, United States.
authors: Maha I
authors: MI
authors: Hamed
authors: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors: Baojie
authors: B
authors: Wan
authors: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors: Scott G
authors: SG
authors: Franzblau
authors: Department of Biological Sciences and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors: Andrew D
authors: AD
authors: Mesecar
authors: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States. Electronic address: cushman@purdue.edu.
authors: Mark
authors: M
authors: Cushman
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D043564:Inorganic Pyrophosphatase / Q000737:chemistry*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis*
chemical_list: D000900:Anti-Bacterial Agents; D014227:Triazines; C093444:1,2,4-triazine; D043564:Inorganic Pyrophosphatase
keywords: 3-(3-Aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine; Antibacterial agents; Inhibitors; Inorganic pyrophosphatase