Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens
| Autor: | Michael N. Lombardo, Amy C. Anderson, Behnoush Hajian, Nigel D. Priestley, Jeremy B. Alverson, Stephanie M. Reeve, Adrienne E. Sochia, Eric W. Scocchera, Santosh Keshipeddy, Dennis L. Wright |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification biology 010405 organic chemistry Organic Chemistry Active site medicine.disease_cause 01 natural sciences Biochemistry Bacterial cell structure 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Enzyme chemistry Staphylococcus aureus Drug Discovery Dihydrofolate reductase Antifolate biology.protein medicine Escherichia coli Gram |
| Zdroj: | ACS Medicinal Chemistry Letters. 7:692-696 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.6b00120 |
| Popis: | Although classical, negatively charged antifolates such as methotrexate possess high affinity for the dihydrofolate reductase (DHFR) enzyme, they are unable to penetrate the bacterial cell wall, rendering them poor antibacterial agents. Herein, we report a new class of charged propargyl-linked antifolates that capture some of the key contacts common to the classical antifolates while maintaining the ability to passively diffuse across the bacterial cell wall. Eight synthesized compounds exhibit extraordinary potency against Gram-positive S. aureus with limited toxicity against mammalian cells and good metabolic profile. High resolution crystal structures of two of the compounds reveal extensive interactions between the carboxylate and active site residues through a highly organized water network. |
| Databáze: | OpenAIRE |
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