Synthesis of [60]Fullerene Hybrids Endowed with Steroids and Monosaccharides: Theoretical Underpinning as Promising anti-SARS-CoV-2 Agents

Abstract

Cyclopropanation reactions between C₆₀ and different malonates decorated with monosaccharides and steroids using the Bingel-Hirsch methodology have allowed the obtention of a new family of hybrid compounds in good yields. A complete set of instrumental techniques has allowed us to fully characterize the hybrid derivatives and to determine the chemical structure of monocycloadducts. Besides, the proposed structures were investigated by cyclic voltammetry, which evidenced the exclusive reductive pattern of fullerene Bingel-type monoadducts. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level of the synthesized conjugates predict the most stable conformation and determine the factors that control the hybrid molecules' geometry. Some parameters such as polarity, lipophilicity, polar surface area, hydrophilicity index, and solvent-accessible surface area were also estimated, predicting its potential permeability and capability as cell membrane penetrators. Additionally, a molecular docking simulation has been carried out using the main protease of SARS-CoV-2 (Mpro) as the receptor, thus paving the way to study the potential application of these hybrids in biomedicine.

Keywords: SARS-CoV-2; [60]Fullerene; molecular docking; sugar steroid hybrids; theoretical calculations.

Scheme 1

Synthesis of hybrid monosaccharide‐steroid‐fullerene (5 a–5 d). (i) Meldrum's acid, toluene, reflux, (ii) monosaccharide (3 a, 3 b or 3 c), BF₃⋅Et₂O or EDC, DCM dry, 1 h, (iii) C₆₀, DBU, CBr₄, toluene, room temperature.

Scheme 2

Selective deprotection. (i) CF₃CO₂H, H₂O, CHCl₃, r.t., 14 h.

Figure 1

Optimized structures of compounds 5 a (a), 5 b (b), 5 c (c), 5 d (d), and 6 (e) using DFT‐D3(BJ) at PBE/6‐311G(d,p) level of theory. Torsion angles (°) are shown in violet and distances in blue (Å).

Figure 2

Non‐covalent interactions of molecules of 5 a (a), 5 b (b), 5 c (c), 5 d (d), and 6 (e). The most important interactions between steroid and sugar moieties are shown as amplification of the zone in each molecule. The isosurfaces with blue color represent strong attractions, green weak attraction forces and red repulsions.

Figure 3

Molecular orbitals involved in the transitions HOMO‐LUMO of 5 a (a), 5 b (b), 5 c (c), 5 d (d), and 6 (e) calculated using DFT‐D3(BJ) method at PBE/6‐311G(d,p) level of theory in the gas phase.

Figure 4

Depiction of the molecular electrostatic potential maps for the optimized structure of 5 a (a), 5 b (b), 5 c (c), 5 d (d), and 6 (e). The red color, represented negative potential, the blue color the positive potential and the green color the uncharged regions.

Figure 5

Superimposed image of hybrids‐Mpro complex with the lower binding energy: 5 b (blue), 5 d (yellow), 6 (green).

Figure 6

Polar interactions of 6 with Mpro residues. The H‐bonds are represented in yellow discontinued lines.