Design, Synthesis, and Microbiological Evaluation of Differently Decorated Pyrazoles Able to Overcome Antimicrobial Resistance and Biofilm Formation

Abstract

Antimicrobial resistance is an urgent global public health threat, killing at least 1.27 million people worldwide and associated with nearly 5 million deaths. Antibiotic resistance has been recently recognized by the WHO as a global health emergency. In this scenario, the research and development of novel derivatives specifically active against resistant pathogens became an urgent need. Pyrazole-based compounds have recently attracted significant interest for their potential antimicrobial activity, particularly against resistant Gram-positive strains such as methicillin-resistant Staphylococcus aureus (MRSA). Based on this evidence, we carried out an in-depth investigation of this chemical class by the synthesis of unreported compounds differently decorated on the pyrazole scaffold. The newly prepared derivatives were tested on a large panel of Gram-negative and Gram-positive strains. Interestingly, pyrazolyl ureas (PUs) 1c and 1h showed excellent minimum inhibitory concentration (MIC) values (8–16 μg/mL) against different Staphylococcus strains and were therefore further evaluated by minimum bactericidal concentration (MBC) determination and time-kill assays and for their ability to inhibit biofilm formation on several MRSA strains. Pyrazole 1c was shown to exert such inhibition at MIC and sub-MIC concentrations (1/2 MIC and 1/4 MIC), highlighting the pharmaceutical potential of this class of compounds against resistant MRSA. Finally, selected PUs did not affect GM-6114 cell viability, thus indicating the lack of cytotoxicity on healthy fibroblasts, and were predicted to possess favorable physicochemical, pharmacokinetic, and drug-likeness profiles.