A novel hydroxytyrosol derivative HT-3 enhances antioxidant and neuroprotective activity through efficient molecular conjugation.

Molecular conjugation is a promising strategy for drug development, which could enhance the efficacy, selectivity, and bioavailability of high-potency compounds through precise structural modifications. Our previous studies demonstrated that hydroxytyrosol (HT) provides excellent neuroprotection in PC12 cells, which is derived from olive oil, and now widely used as a natural food additive. In this study, we rationally designed and synthesized a string of HT derivations by coupling caffeic acid skeletons, and found that HT-3 exhibited the strongest antioxidant activity and superior neuroprotective efficacy via the Keap1/Nrf2/ARE pathway among the HT analogue. Additionally, nanoparticles of HT-3 (HT-3 NPs) were constructed for reducing toxicity and enhancing efficacy, which could enhance blood-brain barrier penetration, accelerate metabolism, and prolong brain retention in mice model of Parkinson's disease. This work would open a new avenue for further investigation of HT analogue.