Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

Cyclooxygenase-2 (COX-2) is a key enzyme in inflammatory pathways and serves as a therapeutic target in the treatment of inflammation-related diseases. Curcumin, a bioactive polyphenol from turmeric, has gained scientific attention due to its potent anti-inflammatory properties, largely mediated through COX-2 inhibition. However, the poor solubility and limited bioavailability of Curcumin limit its potential as a therapeutic agent targeting inflammatory diseases. We used an in silico approach to identify Curcumin-like scaffolds as novel COX-2 inhibitors with improved drug-like properties and therapeutic potential. A pharmacophore model derived from the key binding moieties of Curcumin was used to virtually screen the ZINC-22 database, identifying 237 candidate compounds for further evaluation. Molecular docking further prioritized these compounds to 10 candidates with the highest binding affinities. Most hits obeyed Lipinski’s rules, except for ZINC32605424 and ZINC47133707, which exhibited high LogP and molecular weight, respectively. Toxicity screening indicated that ZINC47133693 and ZINC09499196 exhibited high safety profiles, with ZINC15942488 being highly toxic. Furthermore, certain hits such as ZINC32605424 and ZINC15942488 were predicted to be P-glycoprotein substrates and potential inhibitors of cytochrome P450. Molecular dynamics simulations confirmed the stability of COX-2–ligand complexes, with critical interactions observed at conserved residues Tyr323 and Leu320. Binding energy calculations identified ZINC32605424 as the strongest COX-2 binder, mainly stabilized by Van der Waals forces. Overall, compounds such as ZINC32605424, ZINC08644750, ZINC47133693, and ZINC09499196 demonstrated potent COX-2 inhibition. These candidates show strong potential for further preclinical validation in studies investigating inflammation-related metabolic complications.