1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting d-alanine-d-alanine ligase in bacterio
(2018) European Journal of Medicinal Chemistry — Vol. 159, p. 324-338 (2018)
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- Authors
Thabault, Léopold 
Pochet, Lionel
- Abstract
- (en) The bacterial cell wall and the enzymes involved in peptidoglycan synthesis are privileged targets for the development of novel antibacterial agents. In this work, a series of 1-(2-hydroxybenzoyl)-thiosemicarbazides inhibitors of D-Ala-D-Ala ligase (Ddl) were designed and synthesized in order to target resistant strains of bacteria. Among these, the 4-(3,4-dichlorophenyl)-1-(2-hydroxybenzoyl)-3-thiosemicarbazide 29 was identified as a potent Ddl inhibitor with activity in the micromolar range. This compound, possessing strong antimicrobial activity including against multidrug resistant strains, was proven to act through a bactericidal mechanism and demonstrated very low cytotoxicity on THP-1 human monocytic cell line. Inhibition of Ddl activity by 29 was confirmed in bacterio using UPLC-MS/MS by demonstrating an increase in D-Ala intracellular pools accompanied by a commensurate decrease in D-Ala-D-Ala. Further structure-activity relationships (SARs) studies provided evidence that the hydroxyl substituent in the 2-position (R1) of the benzoylthiosemicarbazide scaffold is essential for the enzymatic inhibition. This work thus highlights the 1-(2-hydroxybenzoyl)-thiosemicarbazide motif as a very promising tool for the development of novel antibacterial compounds acting through an interesting mechanism of action and low cytotoxicity.
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Citations
Ameryckx, A., Thabault, L., Pochet, L., Leimanis, S., Poupaert, J., Wouters, J., Joris, B., Van Bambeke, F., & Frédérick, R. (2018). 1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting d-alanine-d-alanine ligase in bacterio. European Journal of Medicinal Chemistry, 159, 324-338. https://doi.org/10.1016/j.ejmech.2018.09.067 (Original work published 2018)