Design, Synthesis and Biological Evaluation of Novel (E)‐Hydroxystyryl Aralkyl Sulfones as Neuroprotective Agents

Abstract

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.

The Role of Catechol in Caffeic Acid Phenethyl Ester Derivatives for Neuroprotective Effects

“…This suggested that the formation of hydrogen bond may play a more significant role in PhO⋅ stabilization than p‐π conjugation. This observation was further supported by the lack of free radical scavenging activity in compounds with only a single hydroxyl group (including 6 c – d and another compound from the previous study [18b] ). Taking all results into consideration, it was suggested that intramolecular hydrogen bond was inevitable in free radical scavenging.…”

“…The level of NO production reflects the degree of inflammation, and evaluating the inhibitory effect of NO production is a valuable strategy for measuring the anti‐inflammatory activities of target compounds. Lipopolysaccharide (LPS) has been reported to activate BV2 microglial cells to release NO, which can be used in the model of evaluating anti‐inflammatory effects [15d,18b] …”