Synthesis, biofilm formation inhibitory, and inflammation inhibitory activities of new coumarin derivatives.

Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit biofilm formation of Gram positive bacterium (Staphylococcus aureus), Gram negative bacterium (Escherichia coli) as well as the methicillin-resistant S. aureus (MRSA) has been previously described. In the present work, new hybrid coumarin-heterocycles have been synthesized via the reaction of coumarin-6-sulfonyl chloride and 6-aminocoumarin with different small heterocycle moieties. The biological efficacy of the new compounds was evaluated towards their ability to inhibit biofilm formation and their anti-inflammatory properties. The antimicrobial activities of the newly synthesized compounds were tested against Gram positive bacterium (S. aureus ATCC 6538), Gram negative bacterium (E. coli ATCC 25922), yeast (Candida albicans ATCC 10231) and the fungus (Aspergillus niger NRRL-A326). Compounds 4d, 4e, 4f, 6a and 9 showed significant MIC and MBC values against S. aureus, E. coli, C. albicans, and methicillin-resistant S. aureus (MRSA) with especial incidence on compound 9 which surpasses all the other compounds giving MIC and MBC values of (4.88 and 9.76 µg/mL for S. aureus), (78.13 and 312.5 µg/mL for E. coli), (9.77 and 78.13 µg/mL for C. albicans), and (39.06 and 76.7 µg/mL for MRSA), respectively. With reference to the antibiofilm activity, compound 9 exhibited potent antibiofilm activity with IC50 of 60, 133.32, and 19.67 µg/mL against S. aureus, E. coli, and MRSA, (respectively) considering the reference drug (neomycin). Out of all studied compounds, the anti-inflammatory results indicated that compound 4d effectively inhibited nitric oxide production in lipopolysaccharide-(LPS-) stimulated RAW264.7 macrophage cells, giving NO% inhibition of 70% compared to Sulindac (55.2%).

Molecular docking and simulation studies of synthetic protease inhibitors against COVID-19: a computational study.

COVID-19 is the most recent threat to global health. Many people preferred treatment in case of infection instead of vaccination. The inhibition of viral replication is a good strategy for the treatment of COVID-19 infection. 3CLpro and PLpro are two important viral proteases responsible for proteolysis, infection, and replication of the virus. Therefore, targeting of these two enzymes is an attractive way to deal with COVID-19. The aim of this study was to screen some synthetic protease inhibitors to determine an appropriate hit molecule against COVID-19 using molecular docking and molecular dynamic simulations. The strategy depends on docking existing synthetic compounds mostly HIV protease inhibitors against two COVID-19 proteases to identify promising drugs for the treatment of COVID-19. We used protein data bank to obtain the X-ray crystal structure of the most important COVID-19 proteases 3CL pro (PDB ID: 6M2N) and PL pro (PDB ID: 6WX4). In this conceptual context, an attempt has been made to suggest an in silico computational relationship between 50 synthetic protease inhibitors and COVID-19 proteases. Out of 50 screened compounds, the best docking scores were found for these five protease inhibitors BDBM7021, BDBM698, BDBM694, BDBM93239, BDBM700. A 100-ns MD simulation was carried out to assess the stability of COVID-19 proteases and inhibitors, revealing an average RMSD value of 0.7 and favorable binding free energy (MM-GBSA) for all complexes confirming their potency as powerful binders in the COVID-19 proteases' binding pocket. Furthermore, the current results must be confirmed using in-vitro and in-vivo antiviral methods.Communicated by Ramaswamy H. Sarma.