The sulphonamides exert their bacteriostatic effect by competing with p-aminobenzoic acid. To gain a deeper understanding of the structure-activity relationship, the activity and pKa of 50 sulfonamides were measured. This required measurements that were as free from confounding influences as possible – an approach that prefigured much of the work undertaken in target-based drug discovery using all the latest tools of molecular biology since the 1990s. It was found (see graph) that the sulphonamides show a maximum in activity at pKas around 6. This is explained by a requirement for the sulphonamide to be in its ionised form (as might be expected for competition with p-aminobenzoic acid) but that the anionic form must not see the charge so stabilised by delocalisation that the SO2 does not carry a maximal negative charge. These are the kernel of key ideas about understanding and optimising molecular interactions with a binding site that underpin much modern drug design.
“Studies in Chemotherapy. VII. A Theory of the Relation of Structure to Activity of Sulfanilamide Type Compounds” by Bell and Roblin J. Am. Chem. Soc.(1942), 64, , 2905-2917
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