Design, synthesis, and biological evaluation of novel antimicrobials for biofilm eradication

Abstract

The National Institutes of Health reports that biofilms account for 80% of all infections caused by microorganisms and play a substantial role in infections acquired in healthcare settings among humans. Considering the antimicrobial resistance observed toward commercially available antimicrobials, it is crucial to identify effective treatment alternatives for infections associated with biofilms. Small molecule adjuvants show promise in broadening the range of treatment options by enhancing effectiveness against both gram-positive and gram-negative bacteria. A new series of pyrimidotriazine derivatives have been synthesized as novel antimicrobial agents. Their antimicrobial efficacy was assessed against Methicillin-Resistant Staphylococcus aureus (MRSA USA300 LAC) and multidrug-resistant Pseudomonas aeruginosa (PA14) using Kirby-Bauer Disk Diffusion assays. Investigation of antibacterial screening data indicated that pyrimidotriazine compounds show higher inhibition against PA14 than MRSA at 100 mM in DMSO. An optimized synthetic route has been developed to prepare these compounds with high efficiency. Furthermore, tetrahydroimidazo[1,2-a]pyrimidinium derivatives, synthesized via the hydrogenation of imidazo[1,2-a]pyrimidinium salts, also exhibit high bioactivity against MRSA. 2-aminoimidazole heterocycle is a key pharmacophore that demonstrated its capabilities in inhibiting biofilm formation, dispersion, and resensitizes multi-drug-resistant bacterial strains to antibiotic treatments. A library of novel disubstituted 2-aminoimidazoles has been synthesized in excellent yields via an optimized route. The library was tested for the antibiofilm effect against Methicillin- resistant Staphylococcus aureus and Pseudomonas aeruginosa in Kirby-Bauer Disk Diffusion assays.