Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.
The condensation
of phthalic anhydride afforded structurally modified
isoindoline-1,3-dione derivatives with selected amino-containing compounds.
The title compounds (
2
–
30
) have been
characterized by thin-layer chromatography (TLC), infrared spectroscopy,
1
H and
13
C NMR spectroscopy, and mass spectroscopy.
All of the compounds were assessed for their antimycobacterial activity
toward the H37Rv strain by a dual read-out assay method. Among the
synthesized compounds, compound
27
possessed a significant
IC
50
of 18 μM, making it the most potent compound
of the series. The InhA inhibitory (IC
50
) activity of compound
27
was 8.65 μM in comparison to Triclosan (1.32 μM).
Computational studies like density functional theory (DFT) study,
molecular docking, and dynamic simulation studies illustrated the
reactivity and stability of the synthesized compounds as InhA inhibitors.
A quantum-mechanics-based DFT study was carried out to investigate
the molecular and electronic properties, reactivities, and nature
of bonding present in the synthesized compounds and theoretical vibrational
(IR) and isotropic value (
1
H and
13
C NMR) calculations.
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