Synthesis of fluorinated 4H-chromen-4-ones from 2-hydroxyacetophenones and in vitro evaluation of their anticancer and antiviral activity

Abstract

Simple and useful approaches to the synthesis of a large series of 2-X-substituted 4H-chromen-4-one derivatives (X = Me, CF₃, SH, COOMe, COOEt), fluorinated on benzene ring, are reported. Firstly a series of 2-hydroxyacetophenones – the versatile building blocks – was synthesized via Fries rearrangement of acylphenols or by the Sonogashira reaction of polyfluorinated o-iodophenols with TIPS-acetylene, followed by the hydration of the triple bond. Then the transformations of the obtained fluorinated 2-hydroxyacetophenones with ethyl acetate, diethyl oxalate, carbon disulfide and anhydrides of carboxylic acids in the presence of base were investigated. The synthesis of 8-aryl substituted 4H-chromen-4-ones was achieved through the electrophilic iodination of phenolic compounds, followed by the Suzuki coupling of the resulting iodine-containing substrates (2-hydroxyacetophenones or chromene derivatives) with arylboric acids. In this way less reactive biologically important fluorinated 2-hydroxyacetophenones were successfully used extending the scope of the 4H-chromen-4-one family having potential biological activity. Some of the obtained fluorinated chromones were evaluated for cytotoxicity in MCF-7, HepG2, HeLa human cancer cells and in normal human foreskin fibroblast cells (hT'ER B'j1). It has been established that compound 33 has the most pronounced anticancer activity. Screening of all synthesized compounds (35 examples) for their inhibitory activity against influenza A virus A/Puerto Rico/8/34 (H1N1) in the MDCK cell culture revealed that a number of heterocycles (32, 41, 31, 11, 3, 35) differing both in the degree of fluorination and the nature of the substituents exhibit a significant antiviral effect (SI = 12 – 24). Among the studied compounds 2-methyl-4H-chromen-4-ones 31, 35 and 3 showed pronounced antiviral inhibitory activity (IC₅₀ = 2 – 5 μM). The most promising compound 32, containing 6,7,8-trifluorosubstituted scaffold demonstrated low toxicity (CC₅₀ = 823 μM) and high virus inhibition activity (IC₅₀ = 35 μM) caused SI = 24, which allows it to be considered as potential drug-candidate in further in-depth studies.