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

Journal of Enzyme Inhibition and Medicinal Chemistry

Roberto Benoni¹  Nina Franko¹  Barbara Campanini¹  Stefano Bettati²  Andrea Mozzarelli³  Anna Nikitjuka⁴  Aigars Jirgensons⁴  Marco Pieroni⁵  Joana Magalhães⁵  Giannamaria Annunziato⁵  Gabriele Costantino⁶  Anna Karawajczyk⁷ 

[1] Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, Parma, Italy;Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, Parma, Italy;Department of Neurosciences, University of Parma, Parma, Italy;Laboratory of Biochemistry and Molecular Biology, Department of Food and Drug, University of Parma, Parma, Italy;National Institute of Biostructures and Biosystems, Rome, Italy;Institute of Biophysics, Pisa, Italy;Latvian Institute of Organic Synthesis, Riga, Latvia;P4T group, Department of Food and Drug, University of Parma, Parma, Italy;P4T group, Department of Food and Drug, University of Parma, Parma, Italy;Centro Interdipartimentale Misure (CIM)’G. Casnati’, University of Parma, Parma, Ital;Selvita S.A., Park Life Science, Kraków, Poland;

关键词: Antibacterials;    cysteine;    Gram-negatives;    O-acetylserine sulfhydrylase;    permeability;   

DOI  :  10.1080/14756366.2018.1518959

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY