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. 2024 May 6;14(1):10419.
doi: 10.1038/s41598-024-57795-4.

Synthesis and in silico inhibitory action studies of azo-anchored imidazo[4,5-b]indole scaffolds against the COVID-19 main protease (Mpro)

Deepika Geedkar  1 , Ashok Kumar  1 , Pratibha Sharma  2
Affiliations

Synthesis and in silico inhibitory action studies of azo-anchored imidazo[4,5-b]indole scaffolds against the COVID-19 main protease (Mpro)

Deepika Geedkar et al. Sci Rep. .

Abstract

The present work elicits a novel approach to combating COVID-19 by synthesizing a series of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives. The envisaged methodology involves the L-proline-catalyzed condensation of para-amino-functionalized azo benzene, indoline-2,3-dione, and ammonium acetate precursors with pertinent aryl aldehyde derivatives under ultrasonic conditions. The structures of synthesized compounds were corroborated through FT-IR, 1H NMR, 13C NMR, and mass analysis data. Molecular docking studies assessed the inhibitory potential of these compounds against the main protease (Mpro) of SARS-CoV-2. Remarkably, in silico investigations revealed significant inhibitory action surpassing standard drugs such as Remdesivir, Paxlovid, Molnupiravir, Chloroquine, Hydroxychloroquine (HCQ), and (N3), an irreversible Michael acceptor inhibitor. Furthermore, the highly active compound was also screened for cytotoxicity activity against HEK-293 cells and exhibited minimal toxicity across a range of concentrations, affirming its favorable safety profile and potential suitability. The pharmacokinetic properties (ADME) of the synthesized compounds have also been deliberated. This study paves the way for in vitro and in vivo testing of these scaffolds in the ongoing battle against SARS-CoV-2.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Proposed mechanism of inhibition of viral replication by azo-anchored 3,4-dihydroimidazo[4,5-b] indole derivatives 5(a–r) against SARS-CoV-2 main protease (Mpro).
Figure 2
Figure 2
Some representative examples of biologically active azo-containing compounds and FDA-approved drugs.
Scheme 1
Scheme 1
Synthesis of para-amino functionalized azo benzene (1).
Scheme 2
Scheme 2
Ultrasonic-assisted synthesis of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r).
Figure 3
Figure 3
(A) Structure of synthesized ligands 5(a–r), (B) inhibitor (N3), (C) Remdesivir, (D) Paxlovid, (E) Molnupiravir, (F) Chloroquine, and (G) Hydroxychloroquine.
Figure 3
Figure 3
(A) Structure of synthesized ligands 5(a–r), (B) inhibitor (N3), (C) Remdesivir, (D) Paxlovid, (E) Molnupiravir, (F) Chloroquine, and (G) Hydroxychloroquine.
Figure 4
Figure 4
The Secondary structure of the main protease protein (Mpro) of SARS-CoV-2 with the domain I, II, and III (Red circle represents the catalytically active site of Mpro) bind with azo-anchored 3,4-dihydroimidazo[4,5-b] indole derivatives 5(a–r) (Blue Colour), inhibitor (N3) (Yellow Colour) and Standard Drugs (Pink Colour) inside the cavity (green framework).
Figure 5
Figure 5
The hydrogen-bond interaction of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r), inhibitor (N3), and standard drug with main protease protein (Mpro) of SARS-CoV-2.
Figure 5
Figure 5
The hydrogen-bond interaction of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r), inhibitor (N3), and standard drug with main protease protein (Mpro) of SARS-CoV-2.
Figure 5
Figure 5
The hydrogen-bond interaction of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r), inhibitor (N3), and standard drug with main protease protein (Mpro) of SARS-CoV-2.
Figure 6
Figure 6
Cytotoxicity of synthesized compound 5(j) against human normal cell line HEK293.
Figure 7
Figure 7
The bioavailability radars of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r), the native ligand of protease protein (Mpro), and standard drug.
Figure 7
Figure 7
The bioavailability radars of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives 5(a–r), the native ligand of protease protein (Mpro), and standard drug.
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