Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents

Abstract

Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses.

Keywords: COVID-19; antiviral agents; inhibition; nitrogen-containing heterocycles; synthesis; viruses.

Scheme 1

The synthesis of non-nucleoside scaffolds as HIV reverse transcriptase inhibitors.

Figure 1

In vitro phenotypic assay values and corresponding cytotoxicity values against HIV. The molecular docking study of 5a in the binding site of HIV reverse transcriptase [18].

Scheme 2

The synthesis of NINS for anti-HVC activity.

Scheme 3

Synthesis of tryptamine derivative for targeting TK against VZV.

Scheme 4

The synthesis of dipeptide inhibitor against SAR-CoV 3CL^pro [24].

Figure 2

Molecular docking poses and binding interaction of 17 bound to SARS-CoV 3CL^pro [24].

Scheme 5

The synthesis of pyrrole derivatives as glycoprotein inhibitors of HIV-1.

Figure 3

(A) Inhibition assay of tested compounds (R) 21a and (S) 21b with the controls NBD-556 and NBD-11021. (B) Infectivity assay of the compounds and controls with CD4-dependent HIV-1_ADA [29].

Scheme 6

Synthesis of thymidine kinase inhibitors to target HSV.

Figure 4

Docking study of 23a and 23d in the binding site of HSV-1 thymidine kinase [33].

Scheme 7

The synthesis of pyrimido-pyrrolo-quinoxalinedione for inhibiting nucleoprotein of influenza A H1N1 virus.

Figure 5

(a) Chemical structure of nucleozin 3061. (b) The molecular docking study of compound 29 in the influenza A NP [34].

Scheme 8

Synthesis of nucleocapsid inhibitors as anti-HIV/AIDS activity.

Figure 6

The molecular interaction of 33c in the HIV nucleocapsid [38].

Scheme 9

Synthesis of anti-HCV agents targeting HCV polymerase (NS5B).

Figure 7

Molecular interaction of compound 39 in the binding site of HCV polymerase [40].

Figure 8

Comparison of effective percentages of inhibition against HSV infection among compounds 44, 45, and Acyclovir [42].

Scheme 10

Synthesis of pyrimidine derivatives as anti-HSV agents.

Figure 9

The molecular structure of Remdesivir^®.

Figure 10

(A) Percentage of inhibition measured by qRT-PCR and cytotoxicity of Remdesivir^® when used to treat SARS-CoV-2-infected Vero E6 cells. (B) Immunofluorescence assay of viral infection with Remdesivir^® treatment [43].

Figure 11

(A) The binding interaction of ATP with COVID-19 NSP12. (B) The binding interaction of RemTP with COVID-19 NSP12. The green sphere represents the Mg²⁺ ion [44].

Scheme 11

Synthesis of inhibitors against HIV-1 RNase H.

Figure 12

The molecular docking study of compound 50 in the HIV-1 RNase H [49].

Scheme 12

One-pot synthesis of influenza neuraminidase inhibitor.

Figure 13

Molecular interaction of compound 55 in the binding site of H1N1 neuraminidase [52].

Scheme 13

Synthesis of pyrazole derivatives as anti-HBV agents.

Scheme 14

Synthesis of quinoline derivative 64 as HIV RNase H inhibitor.

Figure 14

UV absorbance spectra of compound 64 with different concentrations of Mg²⁺ ion [55].

Scheme 15

Synthesis of the inhibitor to target HCV NS3/4a protease.

Figure 15

Visualization of 66 in the HCV NS3 gt-1b protease active site for interaction with subsites [56].

Scheme 16

Synthesis of quindoline derivative 69 as anti-influenza A agent.

Figure 16

(A) Plaque reduction assay at different concentrations of 69 with PR8, Cal09, Minnesota influenza strains in MDCK cells. (B) Corresponding plaque number from the assay with three viruses at different concentrations [58].

Figure 17

The molecular structure of Chloroquine^® [43].

Figure 18

(A) Percentage of inhibition measured by qRT-PCR and cytotoxicity of Chloroquine^® when treating 2019 n-CoV infected Vero E6 cells. (B) Immunofluorescence assay of viral infection with Chloroquine^® treatment [43].