Objectives: To synthesize and evaluate the anti-inflammatory potential of fifteen naphthoquinones (NQs), determining their ability to inhibitory nitric oxide (NO•) and prostaglandin E2 (PGE2) production. Methods: NQs were screened for their inhibitory effect on NO• and PGE production using LPS-activated RAW 264.7 macrophages. Results: Three linear furanonaphthoquinones (4-6) were identified as potent inhibitors of NO• and PGE2 production, with IC₅₀ values ranging from 0.45 to 2.86 μM (NO•) and 0.38 to 1.65 (PGE2), highlighting the potent activity showed by compound 5 with IC₅₀ values lower than one and high selectivity indices. Conclusions: Synthesized furanonaphthoquinones constitute leading compounds for the design of new anti-inflammatory agents and provide a valuable tool for designing new NQs that might be useful to treat inflammation. The evaluation of compounds 4-6 using in vivo models is warranted.

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