1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting D-alanine-D-alanine ligase in bacterio

Alice Ameryckx, Léopold Thabault, Lionel Pochet, Serge Leimanis, Jacques Poupaert, Johan Wouters, Bernard Joris, Françoise Van Bambeke, Raphaël Frederick

Research output: Contribution to journalArticlepeer-review


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 (R 1) 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.

Original languageEnglish
Pages (from-to)324-338
Number of pages15
JournalEuropean journal of medicinal chemistry / Chimica therapeutica
Issue number5
Publication statusPublished - 1 Nov 2018


  • Antibiotics
  • Antimicrobial agents
  • Benzoylthiosemicarbazides
  • D-alanine-D-alanine ligase inhibitors
  • Structure-activity relationships


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