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.

In the present study,novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents.The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level,while the blood-brain barrier (BBB) permeability was predicted by parallel artificial membrane permeability assay (PAMPA).The results revealed that phenolic hydroxyl groups and double bonds in the structure of CAPE had important effects on neuroprotective activities.Accordingly,a preliminary structure-activity relationship was summarized in this paper.In addition,we observed a significant improvement on BBB permeability.These results provided important references for the structural modification and optimization of CAPE in the future.

(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.

(E)-3,4-diacetoxystyryl aralkyl ketone and sulfone derivatives, with the skeleton of CAPE, were reported as dual inhibitors of HIV-1 IN/CCR5 in our previous study. CAPE could show multifunctional neuroprotective properties through its antioxidant and anti-inflammatory effects. In this study, neuroprotective effects of these dual inhibitors were evaluated, and the biological results revealed that the reduction of conjugated double bonds in ketones did not significantly influence their antioxidant and anti-inflammatory effects. In addition, unsaturated ketones displayed better anti-inflammatory activities than corresponding sulfones. Sulfone compounds 11b and 11d had the best antioxidant effects among all these compounds. Overall, most of these HIV-1 dual inhibitors exhibited both antioxidant and anti-inflammatory activities, and thus had the potential to reduce the morbidity of HIV-associated neurocognitive disorders.