Consider the following Structure Activity Relationships (SAR) of sulfonamide antibiotics and design novel analogs that meet the indicated criteria in parts G-I. The sulfanilamide skeleton is the minimum structural requirement for antibacterial activity of sulfonamide antibiotics. e e e The sulfur atom of the sulfonamide must be directly attached to a phenyl ring. The amino and the sulfonamide functional groups must be oriented para to one another. Adding additional substituents to the phenyl ring produced inactive compounds. Replacing the sulfonamide with a carboxamide reduces the activity. 4 HN sulfanilamide O NH2 Heterocyclic substituents on N1 lead to highly potent sulfanilamide derivatives. A phenyl ring attached to N1 generates a metabolite toxic to the liver. (Can you justify this by utilizing your Organic-2 knowledge??) The N4 amino group can be modified into prodrugs that are converted to the unsubstituted amino group in vivo. The active form of sulfonamide antibiotics is ionized. Maximum activity is observed when the sulfonamide pKa=6.6-7.4. G. Design a novel sulfamethoxazole prodrug expected to be more water soluble, so it can be administered in an IV drip. Provide a brief rationale to explain why the prodrug you design is expected to have greater aqueous solubility. H. Provide a structural rationale to justify the significantly enhanced acidity of sulfamethoxazole relative to sulfapyridine. (Hint from organic-1: Conjugate base stability!!) I. With the goal of optimizing the pKa (and therefore antibacterial activity), design two novel sulfapyridine analogs with suitable modifications to the aromatic heterocycle. Be sure to retain a 6-membered heterocycle with an appropriately positioned nitrogen atom in the new analogs you design.