The antifungal activity of molecules belonging to the arylsulfonamide chemotype has previously been demonstrated. Here, we screened arylsulfonamide-type compounds against a range ofCandidaspp. and further established the structure–activity relationship based on a “hit compound”. A series of four sulfonamide-based compounds, N-(4-sulfamoylbenzyl) biphenyl-4-carboxamide (3), 2,2-diphenyl-N-(4-sulfamoylbenzyl) acetamide (4), N-(4-sulfamoylphenethyl) biphenyl-4-carboxamide (5) and 2,2-diphenyl-N-(4-sulfamoylphenethyl) acetamide (6), were tested against the American Type Culture Collection (ATCC) and clinical strains ofC. albicans,C. parapsilosisandC. glabrata. Based on the fungistatic potential of prototype3, a further subset of compounds, structurally related to hit compound3, was synthesized and tested: two benzamides (10–11), the related amine 4-[[(4-4-((biphenyl-4-ylmethylamino)methyl) benzenesulfonamide (13) and the corresponding hydrochloride,13.HCl. Both amine13and its hydrochloride salt had fungicidal effects againstCandida glabratastrain 33 (MFC of 1.000 mg/mL). An indifferent effect was detected in the association of the compounds with amphotericin B and fluconazole. The cytotoxicity of the active compounds was also evaluated. This data could be useful to develop novel therapeutics for topical use against fungal infections.