ABSTRACT

Keeping in mind, the potentials of hydrazones and their metal complexes as drugs, this research work aims at synthesizing a novel hydrazone and its metal complexes, and evaluation of their virtual screening as a potential antiviral drug for severe acute respiratory syndrome coronavirus 2, SARS-CoV-2. The 2,4-dinitro-N-[(E)-[(E)-3-(2-nitropenyl)prop-2-enyildene]amino]aniline (DNEAA), ligand, and its metal complexes were thus synthesized. Physical measurements, which include, melting point, conductivity and solubility tests and spectroscopic methods; UV-VIS, FTIR, and NMR were adopted to characterize and proffer suitable structures for the ligand and its metal complexes. Thus, crystalline and coloured compounds with yields >80 % and melting points > 150 ⁰C were obtained. Molar conductance values described the complexes as non-electrolytes. In the electronic spectra of the synthesized complexes, shifting of the π→π* transitions to longer or shorter wavelengths indicated the formation of an M-L coordination bond. FTIR spectra showed lowering of the frequency to 1591.6 cm^-1, which indicated that the azomethine group actively took part in co-ordinations. The ¹HNMR signal appeared for imine proton of the azomethine group in the free ligand at δ 9.1ppm and is shifted upfield to 8.7-8.9 for complexes, which indicates the metal-nitrogen coordination. Also, the ¹³CNMR indicated a new δ 125.9 which was absent in the δ values for the ligand, which also showed the involvement of the azomethine group in coordination. An octahedral geometry was therefore suggested for the metal complexes. Binding energies > 9.5 kcal./mol., highlights the success rate of docking operation and positive interactions of the compounds with non-structural protein 1, (NSP 1) of SARS-CoV-2 (PDB ID: 7k3N). Hydrophobic interactions were the most abundant interactions followed by hydrogen bonding. The binding site with the highest druggability score of 0.43 was chosen for the structural display of the metal complexes’ interactions with the 7K3N protease. Zero violations were recorded for the drug likeliness test according to Lipinski's Rule of Five (RO5). In SWISSADME analysis, the DNEAA ligand and its metal complexes were predicted human gastrointestinal absorption (HIA), (bioavailability score ≥0.55) but not accessing the brain, blood-brain barrier (BBB) permeation. The moderately active compounds (the metal complexes) had the highest Topological Surface Area, (TPSA) whereas the comparatively less active compound (the ligand) had the lowest TPSA. Zero PAIN alerts were recorded for the ligand and metal complexes meaning that they are free from promiscuous compounds while Synthetic accessibility (SA) scores for the ligand and metal complexes show that the synthetic routes for these compounds are easy and that the reactions are feasible. LD₅₀(mg/Kg) values (1600,1000,1800,1000,1000, 625, and 1920) for the ligand and metal complexes respectively, showed that all belong to toxicity class 4. The PASS prediction analysis discovered other inhibitory actions of these compounds. Reported toxic/adverse effects for the compounds showed Pa values < 0.7, which indicated their low toxicity. CABSFlex protein flexibility post-ligand study shows that all the protein–ligand complexes evaluated were stable in the physiological conditions studied. Following these findings, we hereby recommend biological studies, pre-clinical and clinical trials against SARS-CoV-2 protease.