Novel pyrimidine-2,4-thiazolidinedione hybrids as dual antimicrobial and anti-virulent agents: synthesis, DNA gyrase B inhibition, and computational investigations.

Globally, antimicrobial resistance (AMR) poses a serious threat to human health and is often associated with poor treatment outcomes. There is an urgent need for effective therapeutic options to address this escalating issue. This study deals with the design and synthesis of new analogs based on the hybridization of the 2-methylpyrimidin-4-amine scaffold with the 5-(substituted-benzylidene)-2,4-thiazolidinedione ring through a methyl linker 9a-n and 10. The antimicrobial evaluation against a diverse panel of Gram-positive, Gram-negative, and fungal strains investigated the promising activity of compounds 9d, 9j, and 9l. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), as well as cytotoxic assessments of the latter derivatives, suggested the bacteriostatic effect against P. aeruginosa of compound 9j, while compounds 9d and 9l demonstrated bactericidal activity against both P. aeruginosa and E. coli, all showing a favorable safety profile. The anti-virulence activity of the hits 9d and 9l was also assessed using various biofilm assays. They effectively suppressed microbial biofilm formation in P. aeruginosa and E. coli strains, with suppression values ranging from 45 to 58%. Furthermore, time-kill kinetics of compound 9l demonstrated bactericidal action in a time-dependent manner in E.coli species. The DNA gyrase B assay of the hits 9d, 9j, and 9l investigated their promising suppression impact with varying IC50 values ranging from 1.967 to 6.403 μg/mL. Molecular docking and molecular dynamic simulation were also carried out for 9j and 9l. Overall, our findings emphasize the pyrimidine-2,4-thiazolidinedione scaffold as a viable antimicrobial option against infections caused by P. aeruginosa and E. coli.