1. Eur J Med Chem. 2018 Nov 5;159:324-338. doi: 10.1016/j.ejmech.2018.09.067. Epub
2018 Sep 28.

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

Ameryckx A(1), Thabault L(1), Pochet L(2), Leimanis S(3), Poupaert JH(1), Wouters
J(4), Joris B(3), Van Bambeke F(5), Frédérick R(6).

Author information: 
(1)Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute
(LDRI), Université Catholique de Louvain (UCLouvain), 73 Avenue Mounier,
B1.73.10, 1200, Bruxelles, Belgium.
(2)Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC),
Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur,
Belgium.
(3)Centre d'Ingénierie des Protéines, Institut de Chimie B6A, Sart-Tilman,
Université de Liège, Liège, Belgium.
(4)Department of Chemistry, Namur Medicine & Drug Innovation Center (NAMEDIC),
Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur,
Belgium.
(5)Pharmacologie Cellulaire et moléculaire (FACM), Louvain Drug Research
Institute (LDRI), Université Catholique de Louvain (UCLouvain), 73 Avenue
Mounier, B1.73.05, 1200 Bruxelles, Belgium.
(6)Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute
(LDRI), Université Catholique de Louvain (UCLouvain), 73 Avenue Mounier,
B1.73.10, 1200, Bruxelles, Belgium. Electronic address:
raphael.frederick@uclouvain.be.

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.

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

DOI: 10.1016/j.ejmech.2018.09.067 
PMID: 30300845