Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives

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.

Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review

“…By inhibiting the liver X receptors (LXRs), its molecule improved the efficacy of all known anti-HCV drugs and demonstrated a significant synergistic effect when combined with either an HCV NS5A inhibitor or interferon [58]. To achieve high yields, Nishiuchi and his colleagues also developed the synthetic antiviral agent NeoB and other derivatives [20].…”

“…Furthermore, neoechinulin A isolated from Aspergillus fumigatus MR2012 from the Red Sea exhibited an IC 50 value of 0.47 µM against SARS-CoV-2, with a similar target to M pro [153]. NeoB, an anti-HBV alkaloid isolated from A. amstelodami, also demonstrated anti-SARS-CoV-2 activity, inhibiting liver X receptors [20]. It has a cytotoxicity threshold (CC 50 ) of greater than 70 µM and an IC 50 of 32.9 µM [20].…”

“…NeoB, an anti-HBV alkaloid isolated from A. amstelodami, also demonstrated anti-SARS-CoV-2 activity, inhibiting liver X receptors [20]. It has a cytotoxicity threshold (CC 50 ) of greater than 70 µM and an IC 50 of 32.9 µM [20]. Furthermore, aspulvinone D, M, and R produced by Cladosporium sp.…”

“…Additionally, microbe-produced vanitaricin A can interact directly with the sodium taurocholate cotransporting polypeptide (NTCP) in HBV, impairing bile acid transport [78,79]. In addition, neoechinulin B bound to the influenza (H1N1) envelope haemagglutinin and disrupted its interaction with the host sialic acid receptor, preventing the influenza virus from attaching to host cells [20,185]. Labyrinthopeptin A prevents both HIV and HSV entry.…”

“…Moreover, natural products also make excellent candidates for drug discovery because their chemical diversity is more closely aligned with drugs than that of synthetic libraries, making them a rich source of pharmacologically active substances that aid in the generation of different drugs [14][15][16]. The success of microbial natural products as drug leads depends on advancements in technologies, such as source and sampling techniques [17], the advancement of nuclear magnetic resonance (NMR) for structure determination [18], fermentation and biotechnology [19], as well as synthesis [20]. Thus, the goal of this review was to provide comprehensive information by incorporating evidence from the available research publications on isolated and identified various natural products derived from microbes, structural scaffold, in vitro or/and in vivo efficacy, and new progress related to their antiviral properties.…”