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.