Structural Modifications of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): New Horizons in Antimicrobial Drug Discovery.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are traditionally recognized for their analgesic and anti-inflammatory effects, mediated by inhibition of cyclooxygenase (COX) enzymes. However, many NSAIDs have been shown to possess intrinsic antimicrobial effects beyond their classical properties. This unexpected activity, together with the rise of antimicrobial resistance, has positioned NSAIDs and their derivatives as promising scaffolds for antimicrobial drug discovery. Additionally, their well-established pharmacological profiles and chemical structures suitable for modification make NSAIDs attractive starting points for developing novel antimicrobial agents. This review, for the first time, focuses exclusively on molecular modifications directly applied to NSAIDs to develop new antimicrobial agents that combat the growing problem of antimicrobial resistance and overcome the limitations of current clinical therapies. These modifications include conjugating commercial NSAIDs with heterocyclic compounds (such as triazole, thiazolidinone, and benzimidazole), functional groups (including hydrazide-hydrazone, Schiff base, hydroxamic acid, amide, and thiosemicarbazide), and other drug molecules (fluconazole, sulfamethoxazole, isoniazid, etc.), resulting in the development of novel antimicrobial agents and an enhanced understanding of their structure-activity relationships. By integrating chemical and biological findings, this review highlights the potential of modifying NSAIDs as a viable strategy to expand the current antimicrobial arsenal and address the growing challenge of antimicrobial resistance.