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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 compound 5 h exhibited prominent antioxidant activity in H2O2 and 6‐OHDA models and higher anti‐inflammatory potency (IC50=7.3 μM) than lead compound 1 (IC50=13.4 μM). Furthermore, compound 5 h displayed predicted CNS (+) blood‐brain barrier permeability (Pe=5.66×10−6 cm s−1) in PAMPA model and low toxicity in PC12 and BV2 cells. These multifunctional properties highlight compound 5 h is a promising candidate for further development against neurodegenerative diseases.

(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 11 b and 11 d 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.

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