Semi-Synthesis and Biological Evaluation of Phyllanthin Derivatives as Potential Neuroprotective Agents

Oxidative stress is responsible for the functional loss and sensory impairment of neurons, which leads to progressive loss of brain and spinal cord cells and contributes significantly to several neurological disorders, thus eventually resulting in brain atrophy and death. This study involves the isolation of lignans, including phyllanthin, hypophyllanthin, and nirtetraline, from Phyllanthus amarus. Furthermore, the phyllanhtin was semi-synthetically modified to give phyllanthin oxadiazole derivatives and was evaluated for neuroprotective activity in scopolamine-injured neuroblastoma-2a (N2A) cells. The biochemical assay for reactive oxygen generation (ROS) production in N2A cells was carried out using 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) dye, and the mitochondrial membrane potential (MMP) was determined in N2A cells by using JC-1 dye. Furthermore, the N2A neuronal deaths were evaluated using acridine orange (AO), ethidium bromide (EtBr), and propidium iodide dyes. Among them, nirtetraline, hypophyllanthin, phyllanthin, and compounds 21 and 31 showed potential neuroprotective effects in N2A cells against scopolamine-induced neurotoxicity by inhibiting ROS production and improving MMP. Moreover, the synthesized compounds were nontoxic to the N2A cell line. Furthermore, in silico docking studies predicted phyllanthin derivatives 21 and 31 exhibit neuroprotective activity by binding to the human NADPH-oxidase 5 enzyme. Thus, compounds 21 and 31 can be considered potential neuroprotective leads.