Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (1) and tenuflorin C (2), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of −18.86 and −18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP.

A biologically guided isolation of secondary metabolites from Cousinia alata Schrenk wild plant growing in Akmola region, Kazakhstan, led to the isolation of the bioactive diterpene grindelic acid (1). Six flavonoids were also isolated and identified as retusine (2), pachipodol (3), jaranol (4), penduletin (5), casticin (6), and 5, 7, 3′-trihydroxy-3, 4′-dimethoxyflavone (7). Penduletin (5) showed moderate cytotoxic activity assay. Grindelic acid exhibited promising cytotoxic activity against the Artemia salina nauplii and antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Salmonella enteritidis. The presence of the essential pharmacophoric features of histone deacetylase (HDAC) inhibitors in the structure of grindelic acid encouraged us to run a molecular docking study against the HDAC enzyme to understand its mechanism of action on a molecular level. Grindelic acid showed a binding mode of interaction similar to that of the cocrystallized ligand and exhibited good binding affinity against HDAC with the binding free energy of −18.70 kcal/mol. The structures of isolated compounds were determined by MS, 1D, and 2D NMR spectroscopy methods. Compounds (1–7) were isolated for the first time from Cousinia genus.

The emergence of the COVID-19 pandemic declared the huge need of humanity for new and effective antiviral drugs. The reported antimicrobial activities of Artemisia sublessingiana encouraged us to investigate the ethanol extract of its aerial parts which led to the isolation of six flavonoids and a sesquiterpenoid. The structures of the isolated compounds were elucidated by EI-MS, 1D, and 2D NMR spectroscopic methods to be (1) eupatilin, (2) 3′,4′-dimethoxyluteolin, (3) 5,7,3′-trihydroxy-6,4′,5′-trimethoxyflavone, (4) hispidulin, (5) apigenin, (6) velutin, and (7) sesquiterpene lactone 8α,14-dihydroxy-11,13-dihydromelampolide. The isolated compounds were in silico examined against the COVID-19 main protease (Mpro) enzyme. Compounds 1–6 exhibited promising binding modes showing free energies ranging from −6.39 to −6.81 (kcal/mol). The best binding energy was for compound 2. The obtained results give hope of finding a treatment for the COVID-19 pandemic.

Ergosterol derivatives exhibited copious promising biological activities. The fungus Gyromitra esculenta is widely distributed in Europe and North America. In order to examine the chemical properties of Gyromitra esculenta, a phytochemical study has been preceded and resulted in the isolation of the steroid, ergosta-5, 22-dien-3β-ol (brassicasterol), from its methanol extract. The complete identification and absolute configuration of the isolated compound have been established by X-ray structural analysis to be (22E, 24R)-24-methylcholesta-5, 22-dien-3beta-ol. The reported cytotoxicity and the great structural similarity of the isolated compound with the cocrystallized ligand of the aromatase enzyme inspired us to run molecular docking studies against that protein. Ergosta-5, 22-dien-3β-ol occupied the target protein with a binding mode almost the same as the cocrystallized ligand and a binding affinity of −33.55 kcal/mol, which was better than that of the cocrystallized ligand (−22.61 kcal/mol). This promising result encouraged us to conduct in silico ADMET and toxicity studies of ergosta-5, 22-dien-3β-ol against 6 models, and the results expected the likeness of the isolated compound to be a drug. In conclusion, ergosta-5, 22-dien-3β-ol has been isolated from Gyromitra esculenta, identified by X-ray structural analysis, and exhibited promising in silico activities against aromatase enzyme.

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2′,4′-trihydroxy-6,7,5′-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein’s active site with a binding energy of −19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and β-sitosterol (4).