Antiviral Activity of N1,N3-Disubstituted Uracil Derivatives against SARS-CoV-2 Variants of Concern

Abstract

Despite the widespread use of the COVID-19 vaccines, the search for effective antiviral drugs for the treatment of patients infected with SARS-CoV-2 is still relevant. Genetic variability leads to the continued circulation of new variants of concern (VOC). There is a significant decrease in the effectiveness of antibody-based therapy, which raises concerns about the development of new antiviral drugs with a high spectrum of activity against VOCs. We synthesized new analogs of uracil derivatives where uracil was substituted at the N1 and N3 positions. Antiviral activity was studied in Vero E6 cells against VOC, including currently widely circulating SARS-CoV-2 Omicron. All synthesized compounds of the panel showed a wide antiviral effect. In addition, we determined that these compounds inhibit the activity of recombinant SARS-CoV-2 RdRp. Our study suggests that these non-nucleoside uracil-based analogs may be of future use as a treatment for patients infected with circulating SARS-CoV-2 variants.

Inactivated Poliovirus Vaccine Booster Reduces the Likelihood of COVID-19 Outcomes in Individuals Primed with Oral Poliovirus Vaccination

“…Overall, 282 participants (age, median [range], 55 [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , …”

“…For instance, remdesivir, an intravenous RdRp inhibitor developed for the Ebola virus, and molnupiravir, an oral drug designed for the influenza virus, are commonly used to treat symptomatic COVID-19 patients [ 17 , 18 , 19 , 20 ]. Since in silico (computer simulations), in vitro (laboratory experiments), and in vivo (studies performed on living organisms) evidence has demonstrated the efficacy of RdRp inhibitors against SARS-CoV-2 variants, it is unsurprising that these drugs have been successful across the various waves of SARS-CoV-2 strains [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. In addition to the exploration of RdRp inhibitors as COVID-19 disease treatments, there has also been interest in using anti-RdRp agents in a prophylactic manner (i.e., to prevent disease and/or provide some protection before an exposure may occur).…”

Major Role of S-Glycoprotein in Providing Immunogenicity and Protective Immunity in mRNA Lipid Nanoparticle Vaccines Based on SARS-CoV-2 Structural Proteins

“…The infectious virus titer in the lungs was determined as previously described [26]. Briefly, 10-fold dilutions of lung homogenates were incubated for an hour on Vero E6 cells.…”

Uracil: A Pharmacophore with Diverse Biological Potential

“…Siniavin et al [35] synthesised analogues of uracil derivatives substituted at N 1 and N 3 positions of the type 8 a-g. The reaction involved treatment of 1-substituted uracils 6 a-g with 4-(ω-bromoalkoxy)benzoic acid methyl esters 7 a-c dissolved in DMF in the presence of potassium carbonate to yield corresponding derivatives of uracil 8 a-g (Scheme 3).…”

“…Siniavin et al [35] . synthesised analogues of uracil derivatives substituted at N 1 and N 3 positions of the type 8 a – g .…”