Synthesis and biological evaluation of clovamide analogues with catechol functionality as potent Parkinson’s disease agents in vitro and in vivo

Abstract • In this study, seven clovamide analogues ( 1 – 7 ) were designed and synthesized, and the neuroprotection of 1 – 7 as well as 8 – 15 (prepared in our previous work) against H 2 O 2 -induced oxidative stress was evaluated in SH-SY5Y cells. Results showed that 1 – 7 with catechol groups exhibited better neuroprotective effects than 8 – 15 , and their EC 50 values ranged from 4.26 to 23.83 μM, especially 1 , indicating that the moiety of catechol governed the activities of these compounds. Furthermore, oral administration of 1 (10 or 20 mg/kg) was demonstrated to possess anti-PD effect through alleviating apoptosis and oxidative stress in vitro and in vivo, and to up-regulate the expression of heme oxygenase-1 (HO-1) via PI3K/AKT/mTOR pathway. Finally, the pharmacokinetic (PK) assessment of 1 was determined in rats. These findings suggested that 1 might be an effective candidate for PD therapy.