Influence of substitution patterns on the antimicrobial properties of pyrrole sulfonamide scaffolds

Two series of sulfonamide derivatives featuring a pyrrol-2-one core were synthesized and evaluated for their antimicrobial and anti-virulence features using Escherichia coli, Pseudomonas aeruginosa, and Candida albicans strains, in planktonic and biofilm growth state. Fourteen substituents were introduced on the pyrrole ring, and the sulfonamide group was shifted from meta- (Series B) to para-position (Series A). Meta-substituted sulfonamides generally exhibited stronger antibacterial activity, likely via selective inhibition of microbial β-/γ-class carbonic anhydrases, while para-substituted derivatives demonstrated superior antifungal activity and antibiofilm potential. Also, series A compounds were particularly effective in inhibiting virulence factors, including haemolysin (S. aureus), lipase and acidification (C. albicans), and lecithinase (P. aeruginosa). Structure-activity relationships revealed that para-substitution aligns with human CA II, correlated with an enhanced antifungal efficacy, whereas meta-substitution favors microbial CA targeting, explaining antibacterial selectivity. Antimicrobial efficacy correlated weakly with lipophilicity and solubility, underscoring species-specific activity. Lipophilicity increased skin permeability but decreased solubility, negatively affecting biocompatibility. However, none of the tested compounds were haemolytic at 1 mg/mL, and all were well tolerated by dermal fibroblasts and keratinocytes at 10 µM. Collectively, these results highlight the dual functionality of these derivatives as selective anti-virulence and antimicrobial agents, while their skin-friendly properties make them promising candidates for the treatment of dermal infections.