A series of novel aromatic sulfonamide derivatives (1–7) were synthesized and characterized by elemental analyses, FT-IR, 1 H NMR, 13C NMR, and LC/ MS techniques. The compounds' quantum mechanical descriptors, surface area, and molecular volume were calculated. All the synthesized compounds were evaluated in vitro as antimicrobial agents against representative strains of gram-positive and gram-negative bacteria and as antifungal agents for yeast by both the disc diffusion and minimal inhibition concentration methods for comparison. All the bacteria and fungi studied were screened against some commercial antibiotics to compare with our chemicals' zone diameters. Quantitative structure–activity relationship studies with multiple linear regression analysis were applied to find the correlation between the different calculated molecular descriptors of the synthesized compounds and biological activity.