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

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 IC 50 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.

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

“…The effort to discover a Sortase A inhibitor has identified various structural scaffolds as potentially clinical useful solutions. These include: 2-phenylbenzofuran-3-carboxamide [ 18 ], 2-phenylbenzo[ d ]oxazole-7-carboxamide [ 19 ], 2-(2-phenylhydrazinylidene)alkanoic acids [ 20 ], benzisothiazolinone [ 21 ], indolethiazolidine [ 22 ], rhodanines [ 23 ], diarylacrylonitriles, triazolo-thiadiazole [ 24 ], and other structures as presented in the reviews of these fields [ 16 , 25 , 26 ].…”

Design and Synthesis of Small Molecules as Potent Staphylococcus aureus Sortase A Inhibitors

“…Several significant small organic molecules have been designed and synthesized, as shown in Figure 2 , with promising IC 50 values. Herein, the concrete synthetic features and the analytic properties for structural identification are described in the order of diarylacrylonitriles [ 38 ], pyridazinones [ 39 ], aryl 3-acryloamides [ 40 ], dihydro-β-carboline [ 41 ], benzisothiazolinones [ 42 ], triazolothiadiazoles [ 43 ], 2-(2-phenylhydrazinylidene)alkanoates [ 44 ], 2-phenyl-benzo[ d ]oxazole-7-carboxamide [ 45 ], 2-phenyl-benzofuran-7-carboxamide [ 46 ], 2-phenylthiazoles [ 47 ], 2, 5-disubstitued thiadiazole [ 48 ], and thiadiazolidinedione [ 49 ].…”

Antibacterial PEGylated Solid Lipid Microparticles for Cosmeceutical Purpose: Formulation, Characterization, and Efficacy Evaluation

“…As expected, MC-RL was as active as MC-L against S. aureus, since RSV did not synergistically contribute to the antimicrobial activity. Notwithstanding, the loading of RSV into the MC-RL might be useful, since better antibacterial properties were reported for RSV in respect to benzoyl peroxide, which is conventionally used to treat acne [6], and the procedures of loading could be optimized to increase RSV amount. Since LIM and RSV are known for inhibiting bacterial growth [6][7][8][9][10][11][12][13], the MC-E, MC-RL, MC-R, and MC-L were analyzed for their antibacterial activity against S. aureus by microbiological assays (Figure 8).…”

“…Even though they are widely used, the prolonged use of chemotherapeutics is the main cause of the spread of antibacterial resistance phenomena in microorganisms, leading to infectious-disease-treatment failure worldwide [4,5]. As a consequence, an additional strategy to contrast antibiotic resistance is the research of new molecules targeting biofilm formation [6,7]. During the last few years, the attention toward the Resveratrol (RSV) has been increasing considerably, due to its proven beneficial properties on human health [8].…”