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Molecules 2016, 21(2), 241; doi:10.3390/molecules21020241

Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives

1
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Sezione di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, Via Archirafi 32, I-90123 Palermo, Italy
2
IEMEST, Istituto Euromediterraneo di Scienza e Tecnologia, Via Emerico Amari 123, I-90139 Palermo, Italy
3
Latvian Biomedical Research and Study Centre, Ratsupites 1 k1, 1067 Riga, Latvia
4
Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, I-95125 Catania, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Peter J. Rutledge
Received: 26 December 2015 / Revised: 5 February 2016 / Accepted: 12 February 2016 / Published: 19 February 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [923 KB, uploaded 19 February 2016]   |  

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. View Full-Text
Keywords: sortase A; biofilms; 2-(2-phenylhydrazinylidene)alkanoic acid derivatives; FRET sortase A; biofilms; 2-(2-phenylhydrazinylidene)alkanoic acid derivatives; FRET
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Maggio, B.; Raffa, D.; Raimondi, M.V.; Cascioferro, S.; Plescia, F.; Schillaci, D.; Cusimano, M.G.; Leonchiks, A.; Zhulenkovs, D.; Basile, L.; Daidone, G. Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives. Molecules 2016, 21, 241.

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