Structure-activity relationship studies of (E)-3,4-dihydroxystyryl alkyl sulfones as novel neuroprotective agents based on improved antioxidant, anti-inflammatory activities and BBB permeability

Abstract ( E )-3,4-dihydroxystyryl alkyl sulfones, as new analogues of neurodegenerative agents, were designed and synthesized. The biological results demonstrated that most of the target compounds preserved antioxidant and anti-inflammatory potency in scavenging reactive free radicals, protecting neuronal cells against neurotoxins such as H 2 O 2 , 6-hydroxydopamine and inhibiting lipopolysaccharide (LPS)-induced over-production of NO. Among these compounds, 6.22 with cyclopentyl propyl exhibited prominent antioxidant activity at low concentration (2.5  μ M) in H 2 O 2 model (cell viability = 94.5%). In addition, 6.22 (IC 50  = 1.6  μ M) displayed better anti-inflammatory activity than that of lead compound 1 (IC 50  = 13.4  μ M). In view of the outstanding performance of 6.22 , the apoptotic rates of H 2 O 2 -damaged PC12 cells were detected by Annexin V-FITC/PI assay. 6.22 showed higher potency in inhibition of apoptosis than 1  at low concentration (2.5  μ M), consisting with the antioxidant and anti-inflammatory models. Furthermore, with the predicted CNS (+) blood-brain barrier (BBB) permeability ( P e  = 6.84 × 10 −6  cm s −1 ), low cytotoxicity and favorable physiochemical properties based on calculation, compound 6.22 can be further developed as a potential multifunctional neuroprotective agent.