A large series of distance-based topological indices has been used for modeling lipophilicity, diuretic activity, and carbonic anhydrase inhibition activity of a library of simple substituted benzene sulfonamides. The results have shown that the topological approach used is quite useful for modeling carbonic anhydrase inhibition and the use of molecular connectivity is the best for this purpose. Excellent results are obtained in multiparametric regressions. The results are critically discussed on the basis of statistical parameters.