Comparative quantitative structure–activity relationship studies on para-substituted aromatic sulphonamides carbonic anhydrase II (CAII) inhibitors are reported in this paper. The study is made utilizing (i) information indices along; (ii) distance-based and connectivity indices and (iii) combination of information, distance-based and connectivity type topological indices. The study has shown that distance-based and connectivity type indices are superior for modelling, monitoring and estimating CAII inhibition. The results are critically discussed using a variety of statistical parameters. Our results show that starting from the mono-parametric regression itself, our results are superior: Furthermore, our methodology allowed carrying out much higher-parametric regressions, yielding a nine-parametric model with R2 as high as 0.8375. The eight-parametric regression, gave R2 = 0.8343. As there is not much difference, we have considered the eight-parametric regression the best.