Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives.
Nishiuchi K, Ohashi H, Nishioka K, Yamasaki M, Furuta M, Mashiko T, Tomoshige S, Ohgane K, Kamisuki S, Watashi K, Kuramochi K.
We have previously reported that neoechinulin B (<b>1a</b>), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the inactivation of the liver X receptors (LXRs) and the resultant disruption of double-membrane vesicles. In this study, a two-step synthesis of the diketopiperazine scaffold of <b>1a</b> was achieved by the base-induced coupling of 1,4-diacetyl-3-{[<i>(tert</i>-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra-<i>n</i>-butylammonium fluoride. Compound <b>1a</b> and its 16 derivatives <b>1b</b>-<b>q</b> were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of <b>1a</b> in MeOH. The antiviral evaluation of <b>1a</b> and its derivatives revealed that <b>1a</b>, <b>1c</b>, <b>1d</b>, <b>1h</b>, <b>1j</b>, <b>1l</b>, and <b>1o</b> exhibited both anti-HCV and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities. The results of this study indicate that the exomethylene moiety on the diketopiperazine ring is important for the antiviral activities. The antiviral compounds can inhibit the production of HCV and SARS-CoV-2 by inactivating LXRs.