From Sulfa Drugs to New Antibacterial Agents: Advances in Chemical Modification of Approved Sulfonamides

Sulfonamides, the oldest synthetic antibacterial agents, specifically target the enzyme dihydropteroate synthase (DHPS), which is essential for the folic acid biosynthesis pathway. In contrast, humans do not use this mechanism as they produce no endogenous folic acid and therefore lack the DHPS enzyme. Despite this unique mechanism and selective action against bacteria, their crucial role in fighting bacterial infections has been diminished by the rise of resistance and allergies to sulfa drugs. To overcome these factors that restrict the application of antibacterial sulfonamides, molecular modification of approved sulfa drugs, such as sulfanilamide, sulfathiazole, and sulfadiazine, appears to be a promising strategy for drug design. This review, for the first time, focuses on the molecular modifications directly performed on sulfa drugs to develop new antibacterial agents that address the resistance and safety problems associated with clinical sulfonamides. These modifications involve the conjugation of commercial sulfa drugs with various heterocycles (triazole, thiazole, thiophene, etc.), functional groups (hydrazone, Schiff base, azo dye, urea/thiourea), phytochemicals (thymol, eugenol, etc.), and drug molecules, leading to new antibacterial candidates and insights into their structure-activity relationships. Given the growing global threat of antibiotic resistance, this review may help restore the importance of traditional sulfa drugs in treating bacterial infections through effective chemical modifications.