A systematic study on sulfonamide derivatives with salicylamide core is presented for possible use in pharmaceutical applications. The molecular structure of eight different compounds has been investigated by FTIR in the frequency range 4000–400 cm⁻¹ to recognize the possible geometrical shape of the molecules needed to uniquely identify the activity of molecule in cancer cell. The electronic charge distribution of these different compounds is further illustrated by UV–Vis spectroscopy in the frequency range 190–1100 nm. The theoretical results obtained from molecular modeling calculations showed that the hydrogen bonds between the OH, CO, NH, and/or CH groups vary from one compound to the other regarding their number and bond length. This confirms the experimental FTIR results regarding the position and broadening of the OH and NH groups due to free rotation of the amide group because of changing the compounds structure by adding different groups to the last phenyl ring. The hydrogen bonds take different directions and values from one compound to the other, which seems to be the most important factor regarding the activity of these different compounds in cancer cell. Both theoretical molecular modeling calculations and FTIR experimental results have strongly evaluated the relation between the chemical structure of 5-chloro-N (4-sulfamoylbenzyl) salicylamide derivatives and their biological activities.