Synthesis of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazines that have antibacterial activity and also inhibit inorganic pyrophosphatase

• Published in: Bioorganic & medicinal chemistry 2014-01, Vol.22 (1), p.406-418
• Main Authors: Lv, Wei, Banerjee, Biplab, Molland, Katrina L., Seleem, Mohamed N., Ghafoor, Adil, Hamed, Maha I., Wan, Baojie, Franzblau, Scott G., Mesecar, Andrew D., Cushman, Mark
• Format: Article
• Language: English
• Subjects: 3-(3-Aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Bacillus anthracis; High-Throughput Screening Assays; Inhibitors; Inorganic pyrophosphatase; Inorganic Pyrophosphatase - chemistry; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Triazines - chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.11.011

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.