A novel coumarin-triazole-thiophene hybrid: synthesis, characterization, ADMET prediction, molecular docking and molecular dynamics studies with a series of SARS-CoV-2 proteins

Abstract

Synthesis, characterization and theoretical studies of a novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1), which was fabricated from 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol and 4-(chloromethyl)-6,7-dimethyl-2H-chromen-2-one, are reported. The resulting compound was characterized by microanalysis, IR, ¹H, and ¹³C APT NMR spectroscopy. The DFT calculations examined the structure and electronic properties of 1 in gas phase. Its reactivity descriptors and molecular electrostatic potential revealed the reactivity and the reactive centers of 1. ADMET properties of 1 were evaluated using the respective online tools. It was established that 1 exhibit positive gastrointestinal absorption properties and negative human blood-brain barrier penetration. The Toxicity Model Report revealed that 1 belongs to toxicity class 4. Molecular docking was additionally applied to study the interaction of 1 with some SARS-CoV-2 proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with Papain-like protease (PLpro). The interaction of 1 with the applied proteins was also studied using molecular dynamics simulations.

Graphical abstract: A novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1) is reported. The structure and electronic properties of 1 were examined by the DFT calculations. ADMET properties of 1 were also evaluated. Molecular docking and molecular dynamics simulations were applied to study interactions of 1 with a series of the SARS-CoV-2 proteins.

Supplementary information: The online version contains supplementary material available at 10.1007/s12039-022-02127-0.

Keywords: Computational study; Coumarin; DFT; Synthesis; Thiophene; Triazole.

Scheme 1

Synthesis of 1.

Figure 1

The ¹H (top) and ¹³C APT (bottom) NMR spectra of 1 recorded in DMSO-d₆ (see Figure 2 for atoms labelling).

Figure 2

Top and side views of the optimized structure of 1, obtained using the DFT/B3LYP/cc-pVDZ method.

Figure 3

Energy levels and views on the electronic isosurfaces of the HOMO and LUMO of the ground state of 1, obtained using the DFT/B3LYP/cc-pVDZ method.

Figure 4

View of the molecular electrostatic potential surface of 1, obtained using the DFT/B3LYP/cc-pVDZ method.

Figure 5

(top-left and bottom) Toxicity results of 1 calculated by ProTox-II. (top-right) Druggability predictions of 1 calculated by SwissADME.

Figure 6

(left) Bioavailability radar for 1 within the domain borders of ADME properties, calculated by SwissADME. The coloured zone of the radar is the suitable physicochemical space for oral bioavailability. (right) BOILED-Egg model of 1 calculated by SwissADME.

Figure 7

2D (left) and 3D (right) views on the interaction of 1 with the applied SARS-CoV-2 proteins.

Figure 8

RMSD, RMSF, Rg, SASA and intermolecular hydrogen bonds analysis profiles of complexes of 1 with Main protease (Mpro), Papain-like protease (PLpro), Nonstructural protein 3 (Nsp_range 207–379-AMP) and Nonstructural protein 3 (Nsp_range 207–379-MES).