Benzoxazole-Acrylonitriles: Dual Bioactivity and DNA Binding from a Sustainable Synthetic Approach

Abstract

Efficient synthesis in aqueous media is employed to prepare targeted compounds to evaluate antiproliferative, antibacterial, and antiviral activity in vitro. The biological activity is influenced by the type and number of substituents placed at phenyl or benzoxazole ring. Acrylonitriles substituted with 3,4-dihydroxy 50, 51, 3,4,5-tryhidroxy 52, 53, and 4-N,N-diethyl-amino 55 groups demonstrate potent antiproliferative effects against cancer cell lines, with IC₅₀ values from 0.7 to 5.8 μM. Their impact on normal cell viability is assessed. The most active benzoxazoles induce DNA damage and are analyzed for their interaction with ct-DNA. UV/Vis titrations, thermal melting assays, and circular dichroism suggest an intercalative mode for the 4-N,N-diethylamino 55 and partial intercalation for the 3,4-dihydroxy 50 and 3,4,5-tryhidroxy derivative 52. Derivative 55 induces apoptosis and cell cycle arrest in cancer cells. Among tested benzoxazoles, significant antiviral activity against HCoV OC43 is observed for the 2-naphthyl 32, 3-indolyl 41 and 42 and p-hydroxy derivative 48 (EC₅₀ from 2.1 to 8.5 μM). Furthermore, antibacterial activity is most effective for the 3,4-dihydroxy and bromine substituted acrylonitrile 51 against S. aureus (MIC 8 μM) and the efflux pump-deleted mutant of E. coli (MIC 4 μM), which is also observed for the hydroxy and bromine substituted 49.