2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors

• Published in: European journal of medicinal chemistry 2019-04, Vol.167, p.200-210
• Main Authors: Cascioferro, Stella, Parrino, Barbara, Petri, Giovanna Li, Cusimano, Maria Grazia, Schillaci, Domenico, Di Sarno, Veronica, Musella, Simona, Giovannetti, Elisa, Cirrincione, Girolamo, Diana, Patrizia
• Format: Article
• Language: English
• Subjects: Anti-Biofilm agents; Anti-virulence agents; imidazo[2,1-b][1,3,4]thiadiazole derivatives; Staphylococcal biofilm inhibitors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.02.007

A class of 36 new 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles was efficiently synthesized and evaluated for their anti-biofilm properties against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923, S. aureus ATCC 6538 and Staphylococcus epidermidis ATCC 12228, and the Gram-negative strains Pseudomonas aeruginosa ATCC 15442 and Escherichia coli ATCC 25922. Many of these new compounds, were able to inhibit biofilm formation of the tested staphylococcal strains showing BIC50 lower than 10 μg/ml. In particular, derivatives 9c and 9h showed remarkable anti-biofilm activity against S. aureus ATCC 25923 with BIC50 values of 0.5 and 0.8 μg/ml, respectively, whereas compound 9aa was the most potent against S. aureus ATCC 6538, with a BIC50 of 0.3 μg/ml. Remarkably, these compounds showed effects in the early stages of the biofilm formation without affecting the mature biofilm of the same strains and the viability of the planktonic form. Their ability in counteracting a virulence factor (biofilm formation) without interfering with the bacterial growth in the free life form make them novel valuable anti-virulence agents. [Display omitted] •New 2-(6-phenylimidazo[2,-1-b][1,3,4]thiadiazol-2-yl)-1H-indoles with anti-biofilm properties were synthesized.•Many compounds inhibited staphylococcal biofilm formation with BIC50 lower than 10 μg/ml.•Compounds 9c and 9h showed BIC50 values of 0.5 and 0.8 μg/ml, respectively, against S. aureus ATCC 25923.•The new derivatives showed a typical anti-virulence profile.