Synthesis and antibacterial profiling of novel pyrimidine-sulfonyl chlorides: a new class of antimicrobials targeting multidrug-resistant bacterial strains.

Bacteria's ability to resist current antibiotics has grave implications for future treatment options. Herein, we report novel pyrimidine-sulfonyl chloride derivatives as potential antimicrobial agents against multi-drug resistance, synthesised through a molecular hybridisation technique. FTIR, 1H-NMR and 13C-NMR analysis data corroborated the structural confirmation of all synthesised compounds. The compounds were screened against a panel of Gram-positive and Gram-negative bacterial strains, including Mycobacterium tuberculosis strains. Cell permeability assays were also performed for MRSA and S. aureus. Among the tested compounds, 6l and 6m exhibited the most potent antibacterial activity against MRSA with a MIC value of 0.2 μg mL-1, more potent than both ciprofloxacin (MIC = 3.91 μg mL-1) and vancomycin (MIC = 0.49 μg mL-1). Further 6j and 6m also displayed good antibacterial activity against clinically isolated MRSA with MIC values of 0.97 and 7.8 μg mL-1, respectively. In contrast, compounds 6g and 6q showed the best activity against Gram-negative bacteria E. hormaechei (MIC = 0.97 μg mL-1), comparable to ciprofloxacin (MIC = 0.2 μg mL-1). In the antimycobacterial studies, compounds 6a, 6c, 6i, 6k and 6l were more potent (MIC = 3.91 μg mL-1) against the extensively drug-resistant Mycobacterium tuberculosis (XDR) strain than the standard drugs used and against H37Rv, compounds 6i and 6k exhibited the best potency with a MIC value of 3.91 μg mL-1. The cell penetration experiment demonstrated that compounds 6h-6m achieved greater than 90% propidium iodide penetration in S. aureus (translating to cell death) at the stated MIC well, whereas less than 80% cell penetration was achieved for methicillin-resistant S. aureus. Computational simulation studies were conducted to validate the biological findings, showing potential binding affinity at the binding site of MurB and FemA enzymes. Thus, pyrimidine-based sulfonyl chloride derivatives exhibited promising anti-microbial and anti-mycobacterial activities.