Design, synthesis and biological evaluation of thiazolyl-halogenated pyrroles or pyrazoles as novel antibacterial and antibiofilm agents.

The formation of biofilm is one of the important factors for bacteria to develop drug-resistant. A series of halogenated-pyrroles or pyrazoles containing thiazole groups as antibacterial agents were designed and synthesized to target biofilms. Among them, compound 8c showed antibacterial activity against various Gram-positive bacteria, particularly against vancomycin-resistant Enterococcus faecalis (MIC ≤0.125 μg/mL). Additionally, this compound significantly inhibited biofilm formation of Staphylococcus aureus and Pseudomonas aeruginosa at sub-MIC doses. Furthermore, compound 8c exhibited significantly lower mammalian cell toxicity compared to pyrrolomycin C and its hepatic microsomal metabolic stability in various species was also evaluated. Further experiment on the infection model of Galleria mellonella proved that the compound was effective in vivo. [Display omitted] • Thiazolyl-halogenated pyrroles or pyrazoles were synthesized for the first time and displayed good antibacterial activity. • Compound 8c , 9b , 10a and 10b effectively inhibited staphylococcal and Pseudomonas aeruginosa biofilm formation at sub-MICs. • Compound 8c showed acceptable PK property, reduced toxicity and effective in vivo activity on Galleria mellonella model. [ABSTRACT FROM AUTHOR]