Synthesis and Antioxidant/Anti-Inflammatory Activity of 3-Arylphthalides

Abstract

Phthalides are a group of compounds with relevant biological activities in different areas such as cytotoxicity, anti-stroke activity, neuroprotection, and inflammation, among others. In this study we designed and synthesized a series of 3-arylphthalide derivatives in order to identify their antioxidant and anti-inflammatory activities. The synthetic methodology was established in terms of atom and step economy through a dehydrative coupling reaction between 3-hydroxyphthalide and different properly functionalized arene rings. The evaluation of the antioxidant activity was performed by the ABTS assay and for the anti-inflammatory activity the inhibition of LPS-induced nitric oxide (NO) production in microglial cells Bv.2 and macrophage cells RAW 264.7 was measured. The synthesized compound 3-(2,4-dihydroxyphenyl)phthalide (5a) showed better antioxidant activity than the Trolox standard and caused strong inhibition of NO production in LPS-stimulated Bv.2 and RAW 264.7 cells. In addition, compound 5a reduced the expression of the pro-inflammatory cytokines Il1b and Il6 in RAW 264.7 cells. These results, which are the first account of the anti-inflammatory activity of 3-arylphthalides, suggest that compound 5a could be a promising candidate for more advanced anti-inflammatory studies.

Palladium-catalyzed C(sp3)-C(sp2) coupling: synthesis of C(3)-arylphthalides

“…Method E is a base-mediated condensation followed by lactone formation (Mola et al 2012). Method F is an example of photochemical Norrish type I cleavage, loss of carbon monoxide, and finally reductive alkylation (Mor et al 2007;Roscini et al 2008;Canonne et al 1988;Ortega et al 2022;Xu et al 2021). Method G is an acid-mediated substitution of the labile C(3) hydroxyl group in phthalide with nucleophiles that include electron-rich aromatic compounds (Canonne et al 1988;Ortega et al 2022;Xu et al 2021).…”

“…Method F is an example of photochemical Norrish type I cleavage, loss of carbon monoxide, and finally reductive alkylation (Mor et al 2007;Roscini et al 2008;Canonne et al 1988;Ortega et al 2022;Xu et al 2021). Method G is an acid-mediated substitution of the labile C(3) hydroxyl group in phthalide with nucleophiles that include electron-rich aromatic compounds (Canonne et al 1988;Ortega et al 2022;Xu et al 2021). However, most of them suffer from one or more drawbacks, like the need for expensive metal catalysts, stoichiometric or excessive amounts of acids or bases, harsh conditions, or low functional group tolerance.…”

A convenient and efficient synthesis of 3-benzofuryl-substituted phthalides

“…[1][2][3] Among various phthalides, 3-substituted phthalides have been proven to possess various biological activities. 2,[4][5][6][7][8][9][10] Representative examples include n-butylphthalide, which has been approved as an anti-ischemic stroke drug in China. 6 (±)-Catalpalactone exhibits specific cytotoxic and antisemitic activities.…”