Design, synthesis, and biological evaluation of novel (E)-1-arylethan-1-one O-((3-arylisoxazol-5-yl) methyl) oxime derivatives as potent non-nucleoside HBV inhibitors

A series of novel O-((3-arylisoxazol-5-yl) methyl) oxime derivatives were synthesized by highly regioselective dipolar cycloadditions of nitrile oxides with (E)-1-arylethan-1-one O-prop-2-yn-1-yl oxime substrates. Results showed that in the formation of (E)-N-hydroxy-3,4-dimethoxybenzimidoyl chloride, chlorinating substitution in phenyl occurred when excess N-chlorosuccinimide. The crystal structure of 10 among the series of compounds revealed it was cis-cyclization product and moiety of-C(CH3) = N -O-was E configuration. As a triclinic crystal, the twist angle between the isoxazol-5-yl ring ( B ) and phenyl ring ( A ) was 57.43, at dihedral angles of 25.22. Screening for anti-HBV activities of these compounds was carried out. The results showed compounds 11, 19 and 12 effectively inhibited HBeAg (IC50 = 158.28 +/- 0.02, 127.51 +/- 0.01, and 213.26 +/- 0.04 respectively). Compounds 11, 19 and 23 manifested stronger inhibition on HBsAg (IC50 = 12.68 +/- 0.06, 61.24 +/- 0.02, and 89.59 +/- 0.02 mu M respectively). Compound 15 was the effctivest inhibition of DNA replication (IC50 = 43.52 +/- 0.02 mu M) among the compounds. Docking study of bioactive compounds with HBV core protein (3KXS) was carried out to explore their interaction.This study determined a new non-nucleoside analogs with inhibition of HBV. (c) 2022 Elsevier B.V. All rights reserved.