Context: High proportion of antibiotic resistance is increasing in bacteria. Aim: Designing and synthesizing novel sulphonamides as anti-bacterial. Settings and Design: Standard drug design process. Methods and Materials: ANNQSAR model, docking studies, applicability domain (Williams plot), distance mapping, HOMO, LUMO surface study, mapped density surface study, NMR (1H and C-13), IR, MASS, CHNS, Kirby-Bauer’s disk diffusion method were used. Statistical analysis used: Fraction of variance (r2), Cross-Validation Test (q2), Standard deviation (s), r2-q2 < 0.3, Quality Factor (Q), Fischer Statistics (F) and Y-Randomization Test were used as a part of this study. Results: Most active compound of the series was 4-[(3-Methoxy-phenylamino)-methyl]- benzenesulfonamide found against E. coli. Conclusions: Novel designed and synthesized sulfonamides act as potential anti-bacterials.