A novel class of (E)-hydroxystyryl aralkyl sulfones were designed and synthesized as neuroprotective agents. Their neuroprotective properties were assessed by several antioxidant models including 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals scavenging model, neuronal protective effects against neurotoxins such as hydrogen peroxide (H2O2), 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium iodide (MPP+). Besides, the anti-inflammatory activity was evaluated by lipopolysaccharide (LPS)-induced nitric oxide (NO) release model in BV2 microglial cells. The result demonstrated that cinnamyl substituted compound5 hexhibited prominent antioxidant activity in H(2)O(2)and 6-OHDA models and higher anti-inflammatory potency (IC50=7.3 mu M) than lead compound1(IC50=13.4 mu M). Furthermore, compound5 hdisplayed predicted CNS (+) blood-brain barrier permeability (P-e=5.66x10(-6) cm s(-1)) in PAMPA model and low toxicity in PC12 and BV2 cells. These multifunctional properties highlight compound5 his a promising candidate for further development against neurodegenerative diseases.

(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 H2O2, 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 μM) in H2O2 model (cell viability = 94.5%). In addition, 6.22 (IC50 = 1.6 μM) displayed better anti-inflammatory activity than that of lead compound 1 (IC50 = 13.4 μM). In view of the outstanding performance of 6.22, the apoptotic rates of H2O2-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 μM), consisting with the antioxidant and anti-inflammatory models. Furthermore, with the predicted CNS (+) blood-brain barrier (BBB) permeability (Pe = 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.