Synthesis and Biological Evaluation of Umifenovir Analogues as Anti-SARS-CoV-2 Agents

Abstract

The unprecedented novel coronavirus disease 2019 (COVID-19) pandemic is a threat to global health and the economy. Since the outbreak of COVID-19, great effort has been made to reposition existing drugs to shorten development timelines, in addition to vaccine development and drug discovery campaigns. Umifenovir is a broad-spectrum antiviral agent used to treat influenza in China and Russia and is currently undergoing clinical trials for the treatment of COVID-19. In this article, the synthesis of umifenovir analogues and their biological evaluation are reported. The inhibitory activities of analogues against the binding of the spike glycoprotein (S-protein) of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to the ACE2 receptor, which is a possible mode of action for umifenovir to inhibit viral infection, were investigated.

Keywords: ACE2 receptor; COVID-19; Indole; SARS-CoV-2; Umifenovir.

Figure 1

Structure of umifenovir (1).

Scheme 1

Synthesis of thioethers 2, 3, and sulfone 4. Reagents and conditions: a) acetic anhydride (Ac₂O), pyridine, reflux, 1 h, 83 %; b) iodomethane (MeI), sodium hydride (NaH), N,N‐dimethylformamide (DMF), 0 °C, 2 h, 87 %; c) N‐bromosuccinimide (NBS), benzoyl peroxide (BPO), carbon tetrachloride (CCl₄), 90 °C, 3 h, 78 %; d) potassium hydroxide (KOH), methanol (MeOH), room temperature (rt), 3 h, 75 %; e) KOH, MeOH, rt, 3 h, 81 %; f) m‐chloroperoxybenzoic acid (mCPBA), dichloromethane (CH₂Cl₂), rt, 5 min., 78 %.

Scheme 2

Synthesis of umifenovir analogues. Reagents and conditions: a) amines, 37 % formaldehyde solution (37 % HCHO), acetic acid (AcOH), reflux, 8 h.

Figure 2

Inhibitory activity of umifenovir analogues. The result was obtained from a single experiment (n=1).