European Journal of Medicinal Chemistry p. 324 - 338 (2018)
Update date:2022-08-15
Topics:
Ameryckx, Alice
Thabault, Léopold
Pochet, Lionel
Leimanis, Serge
Poupaert, Jacques H.
Wouters, Johan
Joris, Bernard
Van Bambeke, Fran?oise
Frédérick, Rapha?l
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.
View MoreContact:+86-532-55689660
Address:qingdao
website:http://www.jairadhesales.com
Contact:0091-79-26431096
Address:309 Harikrupa Tower,Nr old Sharda Mandir Char Rasta,Ellisbridge
website:http://www.hanwayschem.com
Contact:+86-18502787239(whatsapp)
Address:18-1-802, Green Garden, Jianghan District, Wuhan 430023, China
Hangzhou GreenCo Science & Technology Co., Ltd.
Contact:86-571-88257303
Address:1713 Room,Jingui Building,Gudun Road,Xihu District,Hangzhou,China
Shaanxi WuZhiYuan Biological Technology Co.,Ltd
Contact:+86 18791979989
Address:No24.west fengming road,fengming town,qishan county
Doi:10.1016/j.tet.2007.05.004
(2007)Doi:10.1039/c39840001007
(1984)Doi:10.1080/00268948408071832
(1984)Doi:10.1016/0040-4020(84)85007-3
(1984)Doi:10.1002/chem.201905519
(2020)Doi:10.1002/ejoc.200700180
(2007)