Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives.

Kota Nishiuchi,Koichi Watashi,Masateru Furuta,Kazane Nishioka,Takumi Mashiko,Hirofumi Ohashi,Kouji Kuramochi,Masako Yamasaki,Kenji Ohgane,Shinji Kamisuki,Shusuke Tomoshige

doi:10.1021/acs.jnatprod.1c01120

Abstract

We have previously reported that neoechinulin B (1a), 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 1a was achieved by the base-induced coupling of 1,4-diacetyl-3-{[(tert-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra-n-butylammonium fluoride. Compound 1a and its 16 derivatives 1b–q were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of 1a in MeOH. The antiviral evaluation of 1a and its derivatives revealed that 1a, 1c, 1d, 1h, 1j, 1l, and 1o 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.

Highlights

We have previously reported that neoechinulin B (1a), 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
We have previously reported that neoechinulin B (1a), isolated from Eurotium rubrum Hiji[025,2] exhibited antiviral effects against hepatitis C virus (HCV).[3]
Mechanistic studies revealed that this compound disrupted the formation of double-membrane vesicles (DMVs), which are the sites of viral RNA replication, by inhibiting the liver X receptor (LXR)-regulated gene induction required for DMV formation

Summary

■ CONCLUSION

The diketopiperazine scaffold of 1a was successfully constructed in this study. Seventeen 3-arylmethylene-6-methylenepiperazine-2,5-diones (1a−q) were synthesized by the coupling of aldehydes 2 and 1,4-diacetyl-3-{[(tertbutyldimethylsilyl)oxy]methyl}piperazine-2,5-dione (4), fol-. The antiviral activities of 1a−q and 6−8 against HCV and SARS-CoV-2 were evaluated. Compound 1a showed antiviral activities against HCV and SARS-CoV-2. Neoechinulin B derivatives 1b− q, which contain the common diketopiperazine scaffold, showed anti-HCV activity. Among the neoechinulin B derivatives tested in this study, compounds 1l, 1n, and 1p showed more potent anti-HCV activity than 1a without exhibiting any serious cytotoxicity. 1c, 1d, 1h, 1j, 1l, and 1o exhibited anti-SARS-CoV-2 activity. 1c, 1d, 1h, 1j, and 1l exhibited more potent anti-SARS-CoV-2 activity than 1a. The aromatic moieties in 1a−q significantly influence the anti-SARS-CoV-2 activity and cytotoxicity against host cells. CoV-2 are necessary, the results of this study clearly show that natural product 1a is one of the promising lead compounds for the development of broad-spectrum antiviral drugs. For the specific procedures and spectroscopic data for the prepared compounds, see the Supporting Information

General Procedure of Transformation of the Intermediates

■ ACKNOWLEDGMENTS

■ REFERENCES