Synthesis, molecular docking, and binding Gibbs free energy calculation of ß-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease.

The outbreak of novel coronavirus disease 2019 (COVID-19), caused by the novel coronavirus (SARS-CoV-2), has had a significant impact on human health and the economic development. SARS-CoV-2 3CL protease (3CLpro) is highly conserved and plays a key role in mediating the transcription of virus replication. It is an ideal target for the design and screening of anti-coronavirus drugs. In this work, seven ß-nitrostyrene derivatives were synthesized by Henry reaction and ß-dehydration reaction, and their inhibitory effects on SARS-CoV-2 3CL protease were identified by enzyme activity inhibition assay in vitro. Among them, 4-nitro-ß-nitrostyrene (compound a) showed the lowest IC50 values of 0.7297 µM. To investigate the key groups that determine the activity of ß-nitrostyrene derivatives and their interaction mode with the receptor, the molecular docking using the CDOCKER protocol in Discovery Studio 2016 was performed. The results showed that the hydrogen bonds between ß-NO2 and receptor GLY-143 and the π-π stacking between the aryl ring of the ligand and the imidazole ring of receptor HIS-41 significantly contributed to the ligand activity. Furthermore, the ligand-receptor absolute binding Gibbs free energies were calculated using the Binding Affinity Tool (BAT.py) to verify its correlation with the activity of ß-nitrostyrene 3CLpro inhibitors as a scoring function. The higher correlation(r2=0.6) indicates that the absolute binding Gibbs free energy based on molecular dynamics can be used to predict the activity of new ß-nitrostyrene 3CLpro inhibitors. These results provide valuable insights for the functional group-based design, structure optimization and the discovery of high accuracy activity prediction means of anti-COVID-19 lead compounds.

ß-Nitrostyrene derivatives attenuate LPS-mediated acute lung injury via the inhibition of neutrophil-platelet interactions and NET release.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are high-mortality and life-threatening diseases that are associated with neutrophil activation and accumulation within lung tissue. Emerging evidence indicates that neutrophil-platelet aggregates (NPAs) at sites of injury increase acute inflammation and contribute to the development of ALI. Although numerous studies have increased our understanding of the pathophysiology of ALI, there is still a lack of innovative and useful treatments that reduce mortality, emphasizing that there is an urgent need for novel treatment strategies. In this study, a new series of small compounds of ß-nitrostyrene derivatives (BNSDs) were synthesized, and their anti-inflammatory bioactivities on neutrophils and platelets were evaluated. The new small compound C7 modulates neutrophil function by inhibiting superoxide generation and elastase release. Compound C7 elicits protective effects on LPS-induced paw edema and acute lung injury via the inhibition of neutrophil accumulation, proinflammatory mediator release, platelet aggregation, myeloperoxidase activity, and neutrophil extracellular trap (NET) release. NET formation was identified as the bridge for the critical interactions between neutrophils and platelets by confocal microscopy and flow cytometry. This research provides new insights for elucidating the complicated regulation of neutrophils and platelets in ALI and sheds further light on future drug development strategies for ALI/ARDS and acute inflammatory diseases.

ß-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall.

The prevalence of multidrug resistance has been increasingly witnessed during the past few decades. Resistance of human pathogenic fungi against the currently available antifungal agents has increased the frequency of fungal infections and associated mortality rates. The discovery of novel lead antifungal agents is important to challenge multidrug resistance. The present study examined the antifungal potential of chemically synthesized ß-Nitrostyrene derivatives. Among the eight ß-Nitrostyrene derivatives used in this study, SS45, SS46 and SS47 showed strong antifungal potential. The results show that ß-Nitrostyrene derivatives inhibited the growth of different species of human pathogenic Candida, particularly the highly prevalent C. albicans, C. glabrata and the emerging pathogenic C. auris species. Moreover, ß-Nitrostyrene derivatives also show strong antifungal activities against drug-resistant clinical isolates and drug transporter overexpressing fungal species. The drug susceptibility assays revealed that ß-Nitrostyrene derivatives are fungicidal and show the synergy of action when combined with antifungal drugs caspofungin and fluconazole. The transcriptomic study performed on C. albicans in the presence of ß-Nitrostyrene derivatives revealed the differential expression of genes related to cell wall metabolism. Mechanistically, ß-Nitrostyrene derivatives impact cell wall morphology, enhance ROS generation and modulate drug efflux. Collectively this study reveals that ß-Nitrostyrene derivatives have strong antifungal potential with a particular mode of activity similar to known cell wall perturbing antifungal agents and thus can be exploited as promising potential antifungal agents for further studies.

One-pot Multicomponent Synthesis of pyrrolo[1,2-d][1,4]benzoxazines and pyrrolo[1, 2-a]pyrazines in Water Catalyzed by Fe3O4@SiO2@L-Arginine-SA Magnetic Nanoparticles.

AIMS: Synthesis of pyrrolo[1,2-d][1,4]benzoxazines and pyrrolo[1,2-a]pyrazines using magnetic nanoparticles. BACKGROUND: One-pot, three component reaction for the synthesis of pyrrolo[1,2-d][1,4]benzoxazines and pyrrolo[1,2-a]pyrazines is reported. For the synthesis of pyrrolo[1,2-d][1,4]benzoxazines use of 2- aminophenols, dialkylacetylenedicarboxylates and ß -nitrostyrene derivatives and Pyrrolo[1,2-a]pyrazines synthesized from reaction of ethylenediamine, dialkylacetylenedicarboxylates and ß-nitrostyrene derivatives is discussed. MATERIALS AND METHODS: 2-aminophenol (0.5 mmol) and dimethylacetylenedicarboxylate (0.5 mmol) in water (3 ml) were stirred at room temperature for 10 min. Then, ß-nitrostyrene (0.5 mmol) and Fe3O4@SiO2@LArginine- SA MNPs (0.07 g) were added and the mixture was refluxed for 5 h. After completion of the reaction, the mixture was cooled to room temperature and the catalyst was separated with external magnet and product extracted with dichloromethane. More purification of products was performed by column chromatography (nhexane/ ethyl acetate 4:1). Ethylenediamine (0.6 mmol) was added to dialkylacetylenedicarboxylate (0.6 mmol) in 3 ml water and was stirred for 10 min at room temperature. Later, ß -nitrostyrene (0.5 mmol) and Fe3O4@SiO2@L-Arginine-SA MNPs (0.06 g) were added to mixture reaction and refluxed for 3 h. After completion, the mixture reaction was cooled to room temperature and the catalyst was separated by an external magnet. Then, the product was extracted with dichloromethane. For more purification column chromatography was used (n-hexane/ethylacetate 1:1). RESULTS AND DISCUSSIONS: In this research, we have synthesized new derivatives of pyrrolo[1,2- d][1.4]benzoxazines and pyrrolo[1,2-a]pyrazines in green conditions consisting of use of water as a green solvent and magnetic nanoparticles. CONCLUSION: In this research, we have synthesized new derivatives of pyrrolo[1,2-d][1.4]benzoxazines and pyrrolo[1,2-a]pyrazines in green conditions consisting of use of water as a green solvent and magnetic nanoparticles which were easily separated from mixture with an external magnet and had the capability to be recovered and reused. Also, in this work, the yield was good and the time of reactions was low compared with prior research.