Synthesis and production of hydroxytyrosol derivatives with potent anti-inflammatory activities

Hydroxytyrosol (HT) is a potent antioxidant compound abundantly found in various parts of olives. However, its high hydrophilicity hampers its formulation and delivery in nutraceutical and pharmaceutical applications. In this study, HT was chemically modified via esterification with benzoic acid derivatives to form HT-benzoate compounds. Sixteen HT derivatives (3a-3p) were produced with yields up to 72%. Structures were confirmed by NMR and HMRS analyses, and all compounds exhibited anti-inflammatory activity with nitric oxide inhibition. Among these, eight compounds showed anti-inflammatory activities with IC₅₀ values of 3.46-5.95 μM, showing up to 10-fold increase compared to the precursor. All compounds were non-cytotoxic except compound 3d. Compounds 3a and 3l significantly suppressed the expression of key inflammatory genes such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). These findings indicate that these HT derivatives may serve as promising anti-inflammatory candidates for further pharmacological evaluation.