4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth
| Autor: | Adam Yasgar, Michael D. Burkart, Thomas Daniel, Timothy L. Foley, Matias S. Attene-Ramos, William Leister, Ganesha Rai, Anton Simeonov, Nicolas M. Kosa, Ajit Jadhav, Heather L. Baker, David J. Maloney |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Stereochemistry Pyridines Metabolite Secondary Metabolism Transferases (Other Substituted Phosphate Groups) Bacillus subtilis Microbial Sensitivity Tests medicine.disease_cause Gram-Positive Bacteria Article 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Bacterial Proteins In vivo Drug Discovery Drug Resistance Bacterial medicine Escherichia coli Structure–activity relationship Animals Humans Secondary metabolism 030304 developmental biology 0303 health sciences biology 030306 microbiology Thiourea Drug Synergism Dipeptides biology.organism_classification 3. Good health Anti-Bacterial Agents Biochemistry chemistry Microsomes Liver Molecular Medicine Efflux Antibacterial activity |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 |
| Popis: | 4'-Phosphopantetheinyl transferases (PPTases) catalyze a post-translational modification essential to bacterial cell viability and virulence. We present the discovery and medicinal chemistry optimization of 2-pyridinyl-N-(4-aryl)piperazine-1-carbothioamides, which exhibit submicromolar inhibition of bacterial Sfp-PPTase with no activity toward the human orthologue. Moreover, compounds within this class possess antibacterial activity in the absence of a rapid cytotoxic response in human cells. An advanced analogue of this series, ML267 (55), was found to attenuate production of an Sfp-PPTase-dependent metabolite when applied to Bacillus subtilis at sublethal doses. Additional testing revealed antibacterial activity against methicillin-resistant Staphylococcus aureus , and chemical genetic studies implicated efflux as a mechanism for resistance in Escherichia coli . Additionally, we highlight the in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetic profiles of compound 55 to further demonstrate the potential utility of this small-molecule inhibitor. |
| Databáze: | OpenAIRE |
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