Natural phenolic scaffolds as COX-1/COX-2 modulators: Curcuminoids, cinnamates, hydroquinone/resorcinol analogues, and stilbenes

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammation but are often associated with a range of adverse effects. Moreover, most conventional NSAIDs selectively inhibit either cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), often without a balanced modulation of both isoforms. These limitations have spurred growing interest in natural products and their derivatives as alternative anti-inflammatory agents. This review provides a critical overview of selected classes of natural compounds - such as curcumin, cinnamic acid derivatives, hydroquinone, resorcinol, resveratrol, and their derivatives - with reported COX-1 and COX-2 inhibitory activity. Particular attention is given to their halfmaximal inhibitory concentration (IC50), selectivity index (SI), and structure-activity relationships, which highlight the chemical features underlying their bioactivity. By consolidating current findings, this review critically evaluates the therapeutic potential of natural products as alternatives to conventional NSAIDs and discusses perspectives for future research, including the need for toxicity assessment and exploration of additional pharmacological benefits such as antioxidant and anticancer activities. We emphasize assay-contextualized potency/selectivity and concise SAR rather than an exhaustive catalogue, to guide rational derivatization.