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. 2023 Dec;38(1):2202357.
doi: 10.1080/14756366.2023.2202357.

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N-(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies

Ahmed A Al-Karmalawy  1 , Dalia S El-Gamil  1 , Rabeh El-Shesheny  2 , Marwa Sharaky  3 , Radwan Alnajjar  4   5   6 , Omnia Kutkat  2 , Yassmin Moatasim  2 , Mohamed Elagawany  7 , Sara T Al-Rashood  8 , Faizah A Binjubair  8 , Wagdy M Eldehna  9   10 , Ayman M Noreddin  11   12 , Mohamed Y Zakaria  13
Affiliations

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N-(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies

Ahmed A Al-Karmalawy et al. J Enzyme Inhib Med Chem. 2023 Dec.

Abstract

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC50 and inhibitory concentration 50 (IC50) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with an IC50 value of 0.73 μg/mL. Moreover, F3e was selected for further elucidation of a possible mode of action where the results showed that it exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition. Besides, molecular docking and MD simulations towards the SARS-CoV-2 Mpro were performed. Finally, a structure-activity relationship (SAR) study focussed on studying the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide in addition to compound contraction on SARS-CoV-2 activity.HighlightsEmulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g).The most potent 3e-loaded EMLs (F3e) showed an IC50 value of 0.73 μg/mL against SARS-CoV-2.F3e exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition.Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA calculations were performed.Structure-activity relationship (SAR) study was discussed to study the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide on the anti-SARS-CoV-2 activity.

Keywords: N-(5-nitrothiazol-2-yl)-carboxamide; SAR; anti-SARS-CoV-2; emulsomes; mechanistic study.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Examples of reported potential Mpro inhibitors and how they function against SARS-CoV-2.
Scheme 1.
Scheme 1.
Chemical synthesis of the previously designed 3a–g candidates to combat COVID-19.
Figure 2.
Figure 2.
Rationale design for the synthesised N-(5-nitrothiazol-2-yl)-carboxamido derivatives as potential inhibitors of SARS-CoV-2 Mpro and the promising effect of the emulsomal nanoparticles.
Figure 3.
Figure 3.
3D surface plot of the impact of (A) lipid core amount, (B) PC amount, and (C) Brij 52 amount on EE% of 3b-loaded EMLs.
Figure 4.
Figure 4.
3D surface plot of the impact of (A) lipid core amount, (B) PC amount, and (C) Brij 52 amount on PS of 3b-loaded EMLs.
Figure 5.
Figure 5.
3D surface plot of the impact of (A) lipid core amount, (B) PC amount, and (C) Brij 52 amount on ZP of 3b-loaded EMLs.
Figure 6.
Figure 6.
DSC thermograms of pure compound 3b, blank F6, and 3b-loaded F6.
Figure 7.
Figure 7.
In vitro drug release profile of 3b from optimised formula F6 compared to the drug dispersion.
Figure 8.
Figure 8.
In vitro assessment of cytotoxicity and anti-SARS-CoV-2 activity of F3a–g in Vero E6 cells via MTT assay (hCoV-19/Egypt/NRC-03/2020 (accession number on GSAID: EPI_ISL_430820)).
Figure 9.
Figure 9.
Mode of action of the most potent formulation (F3e) against SARS-CoV-2.
Figure 10.
Figure 10.
The RMSD of complexes (3a, 3b, 3c, 3d, 3e, 3f, 3g, and Co) for SARS-CoV-2 Mpro as a function of simulation time (200 ns).
Figure 11.
Figure 11.
The RMSD of ligands (3a, 3b, 3c, 3d, 3e, 3f, 3g, and Co) for SARS-CoV-2 Mpro, respectively, as a function of simulation time (200 ns).
Figure 12.
Figure 12.
Histogram describing the binding interactions between the SARS-CoV-2 Mpro and its ligand during the simulation time of 200 ns for (A) 3d, (B) 3e, (C) 3g, and (D) Co.
Figure 13.
Figure 13.
Heat map showing the total number of SARS-CoV-2 Mpro-ligand interactions all over the simulation time of 200 ns for (A) 3d, (B) 3e, (C) 3g, and (D) Co.
Figure 14.
Figure 14.
SAR summary for the synthesised N-(5-nitrothiazol-2-yl)-carboxamido derivatives as potential inhibitors of SARS-CoV-2 Mpro.
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