Evaluation of Antibacterial Functionalized Dihydropyrimidine Photoaffinity Probes Toward Mechanism of Action Studies.

Autor:	Russo CM; Department of Chemistry, Villanova University, Villanova, Pennsylvania 19085, United States., Boyer ZW; Department of Chemistry, Villanova University, Villanova, Pennsylvania 19085, United States., Scheunemann K; Department of Chemistry and Biotechnology, University of Wisconsin-River Falls, River Falls, Wisconsin 54022, United States., Farren J; Department of Chemistry and Biotechnology, University of Wisconsin-River Falls, River Falls, Wisconsin 54022, United States., Minich A; School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Wenthur CJ; School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., O'Reilly MC; Department of Chemistry, Villanova University, Villanova, Pennsylvania 19085, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Jun 20; Vol. 15 (7), pp. 1094-1101. Date of Electronic Publication: 2024 Jun 20 (Print Publication: 2024).
DOI:	10.1021/acsmedchemlett.4c00173
Abstrakt:	Antibiotic-resistant bacteria are a global health concern, necessitating the development of antibiotics working through new or underutilized mechanisms. Functionalized amino dihydropyrimidines have previously demonstrated potential as antibacterial agents, but they had limited potency, and their biological mechanism was not understood. To further evaluate their potential, focused libraries were prepared and screened for bacterial growth inhibition, and these compounds provided additional insights into the structure-activity relationships, allowing for the preparation of compounds that inhibited all strains of Staphylococcus aureus with an MIC of 2 μg/mL. After eliminating the proposed mechanism of dihydrofolate reductase inhibition, trifluoromethyl diazirine photoaffinity probes were synthesized to investigate their mechanism, and these were tested to ensure the photolabile group did not impact the antibacterial activity. Finally, the compounds were screened for hemolysis and mammalian cytotoxicity. While they lacked nonspecific membrane rupturing activity, many of the compounds showed significant mammalian cytotoxicity, indicating further development will be required to render them selective for bacteria. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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