Wei Lv1, Biplab Banerjee1, Katrina L Molland2, Mohamed N Seleem3, Adil Ghafoor3, Maha I Hamed3, Baojie Wan4, Scott G Franzblau4, Andrew D Mesecar2, Mark Cushman5. 1. 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. 2. Department of Biological Sciences and The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States. 3. Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, United States. 4. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States. 5. 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.
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.
Inorganic pyrophosphatases are potentn class="Chemical">ial targets for the development of novel antibacterial agents. A pyrophosphatase-coupled high-throughput screening assay intended to detect o-succinyl benzoic acid coenzyme A (OSBCoA) synthetase inhibitors led to the unexpected discovery of a new series of novel inorganic pyrophosphataseinhibitors. Lead optimization studies resulted in a series of3-(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.
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