N-Thiolated β-lactam antibacterials: Effects of the N-organothio substituent on anti-MRSA activity

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Abstract

A study on the structure-activity profiles of N-thiolated β-lactams 1 is reported which demonstrates the importance of the N-organothio moiety on antibacterial activity. Our results indicate that elongation of the N-alkylthio residue beyond two carbons, or extensive branching within the organothio substituent, diminishes antibacterial effects. Of the derivatives we examined, the N-sec-butylthio β-lactam derivative 5g possesses the strongest growth inhibitory activity against methicillin-resistant Staphylococcus aureus strains. Sulfur oxidation state is important, as the N-sulfenyl and N-sulfinyl groups provide for the best antibacterial activity, while lactams bearing the N-sulfonyl or N-sulfonic acid functionalities have much weaker or no anti-MRSA properties. Stereochemistry within the organothio chain does not seem to be a significant factor, although for N-sec-butylthio β-lactams 15a-d, the 3R,4S-lactams 15c, d are more active than the 3S,4R-stereoisomers 15a, b in agar diffusion experiments. The N-methylthio lactams are the most sensitive to the presence of glutathione, followed by N-ethylthio and N-sec-butylthio lactams, which indicates that bioactivity and perhaps bacterial selectivity of the lactams may be related to the amount of organothiols in the bacterial cell. These results support the empirical model for the mechanism of action of the compounds in which the lactam transverses the bacterial membrane to deliver the organothio moiety to its cellular target. © 2006 Elsevier Ltd. All rights reserved.

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Heldreth, B., Long, T. E., Jang, S., Reddy, G. S. K., Turos, E., Dickey, S., & Lim, D. V. (2006). N-Thiolated β-lactam antibacterials: Effects of the N-organothio substituent on anti-MRSA activity. Bioorganic and Medicinal Chemistry, 14(11), 3775–3784. https://doi.org/10.1016/j.bmc.2006.01.029

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