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Refining the structure−activity relationships of 2-phenylcyclopropane carboxylic acids as inhibitors of O-acetylserine sulfhydrylase isoforms

Authors :
Joana Magalhães
Nina Franko
Giannamaria Annunziato
Marco Pieroni
Roberto Benoni
Anna Nikitjuka
Andrea Mozzarelli
Stefano Bettati
Anna Karawajczyk
Aigars Jirgensons
Barbara Campanini
Gabriele Costantino
Source :
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 34, Iss 1, Pp 31-43 (2019)
Publication Year :
2019
Publisher :
Taylor & Francis Group, 2019.

Abstract

The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase – a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability. Therefore, we rationally modified the structure of the hit compound with the aim of promoting their passage through the outer cell membrane porins. The new series was evaluated on the recombinant enzyme from Salmonella enterica serovar Typhimurium, with several compounds able to keep nanomolar binding affinity despite the extent of chemical manipulation.

Details

Language :
English
ISSN :
14756366 and 14756374
Volume :
34
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Enzyme Inhibition and Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
edsdoj.7f454e5900149429f6d3c19ae6529c0
Document Type :
article
Full Text :
https://doi.org/10.1080/14756366.2018.1518959