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ACS Med Chem Lett. 2016 May 5;7(7):692-6. doi: 10.1021/acsmedchemlett.6b00120. eCollection 2016 Jul 14.

Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens.

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Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06268, United States.
Deptartment of Chemistry, University of Montana , Missoula, Montana 59812, United States.


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.


Dihydrofolate reductase; Escherichia coli; MRSA; Staphylococcus aureus; antifolate; methotrexate; trimethoprim

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