The effect of structural variations of heteroleptic Cu(II) complexes of tri‐dentate unsymmetrical Schiff‐base main ligands with pyridine or bithiazole co‐ligands on molecular docking against SARS‐CoV‐2 and its Omicron variant main proteases

Meso‐1,2‐diphenyl‐1,2‐ethylenediamine was reacted with salicylaldehyde derivatives, copper(II) perchlorate, and pyridine to produce various four‐coordinated heteroleptic [Cu (SBn)(py)]ClO4 (n = 1–4) complexes. Ligand exchange of the monodentate pyridine with bidentate 2,2′‐dimethyl‐4,4′‐bithiazole (BTZ) produced other new series of five‐coordinated [Cu (SBna)(BTZ)]ClO4 complexes. Elemental analysis, Fourier‐transform infrared spectroscopy (FT‐IR), and ultraviolet–visible (UV–Vis) spectroscopy were used to identify the complexes. The crystal structures of 1a and 2a were also determined by single‐crystal X‐ray crystallography (SCXRC). The inhibitory potential of these complexes against SARS‐CoV‐2 and its omicron variant main proteases (PDB IDs: 6LU7 and 7TLL, respectively) was investigated by means of molecular‐docking modeling. According to the estimated free binding energy (EFBE), the order of binding energies were (3) > (3a) > (1a) > (1) > (2a) > (4a) > (4) > (2) for 6LU7 and (1a) > (3) > (1) > (4) > (2) > (4a) > (2a) > (3a) for 7TLL. The complexes (1a) for 6LU7 and (3) for 7TLL with electronegative Br substituents were at the top of the series and had the most negative ΔGbinding. The EFBE of four conventional corona‐virus medicines, that is, remdesivir, hydroxychloroquine, dexamethasone, and AstraZeneca were also obtained and compared with the synthesized complexes. The EFBE of the complexes were comparable to standard drugs.

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