1. Discovery of a new class of sortase a transpeptidase inhibitors to tackle gram-positive pathogens: 2-(2-phenylhydrazinylidene)alkanoic acids and related derivatives
- Author
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Fabiana Plescia, Demetrio Raffa, Dmitrijs Zhulenkovs, Maria Grazia Cusimano, Benedetta Maggio, Ainars Leonchiks, Giuseppe Daidone, Domenico Schillaci, Stella Cascioferro, Maria Valeria Raimondi, Livia Basile, Maggio, B., Raffa, D., Raimondi, M., Cascioferro, S., Plescia, F., Schillaci, D., Cusimano, M., Leonchiks, A., Zhulenkovs, D., Basile, L., and Daidone, G.
- Subjects
sortase A ,biofilms ,2-(2-phenylhydrazinylidene)alkanoic acid derivatives ,FRET ,0301 basic medicine ,Staphylococcus aureus ,Stereochemistry ,Pharmaceutical Science ,Related derivatives ,medicine.disease_cause ,Settore BIO/19 - Microbiologia Generale ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Inhibitory Concentration 50 ,03 medical and health sciences ,chemistry.chemical_compound ,2-(2-phenylhydrazinylidene)alkanoic acid derivative ,Anti-Infective Agents ,Bacterial Proteins ,lcsh:Organic chemistry ,Staphylococcus epidermidis ,Amide ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,IC50 ,Gram ,biology ,010405 organic chemistry ,Chemistry ,Biofilm ,Sortase A ,Organic Chemistry ,Aminoacyltransferases ,biology.organism_classification ,Settore CHIM/08 - Chimica Farmaceutica ,Phenylhydrazines ,0104 chemical sciences ,Cysteine Endopeptidases ,030104 developmental biology ,Chemistry (miscellaneous) ,Molecular Medicine - Abstract
A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM.
- Published
- 2016