Discovery of a new class of sortase a transpeptidase inhibitors to tackle gram-positive pathogens: 2-(2-phenylhydrazinylidene)alkanoic acids and related derivatives

6533b82afe1ef96bd128b8c2

RESEARCH PRODUCT

Discovery of a new class of sortase a transpeptidase inhibitors to tackle gram-positive pathogens: 2-(2-phenylhydrazinylidene)alkanoic acids and related derivatives

Fabiana Plescia Demetrio Raffa Dmitrijs Zhulenkovs Maria Grazia Cusimano Benedetta Maggio Ainars Leonchiks Giuseppe Daidone Domenico Schillaci Stella Cascioferro Maria Valeria Raimondi Livia Basile

subject

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 Staphylococcus epidermidis medicine Enzyme Inhibitors Physical and Theoretical Chemistry IC50 Gram biology 010405 organic chemistry Chemistry Biofilm Sortase A Organic Chemistry Biofilm Aminoacyltransferases biology.organism_classification Settore CHIM/08 - Chimica Farmaceutica 2-(2-phenylhydrazinylidene)alkanoic acid derivatives Phenylhydrazines 0104 chemical sciences Cysteine Endopeptidases 030104 developmental biology Chemistry (miscellaneous)Staphylococcus aureus Sortase A FRET Molecular Medicine biofilms

description

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.

year	journal	country	edition	language
2016-02-19

10.3390/molecules21020241 http://hdl.handle.net/10447/179975