Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors.

The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4-6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4-6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4-6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2-6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2-6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.

GANE can Improve Lung Fibrosis by Reducing Inflammation via Promoting p38MAPK/TGF-ß1/NF-κB Signaling Pathway Downregulation.

There is a trend to use nanoparticles as distinct treatments for cancer treatment because they have overcome many of the limitations of traditional drug delivery systems. Gallic acid (GA) is an effective polyphenol in the treatment of tissue injuries. In this study, GA was loaded onto niosomes to produce gallic acid nanoemulsion (GANE) using a green synthesis technique. GANE's efficiency, morphology, UV absorption, release, and Fourier-transform infrared spectroscopy (FTIR) analysis were evaluated. An in vitro study was conducted on the A549 lung carcinoma cell line to determine the GANE cytotoxicity. Also, our study was extended to evaluate the protective effect of GANE against lipopolysaccharide (LPS)-induced pulmonary fibrosis in rats. GANE showed higher encapsulation efficiency and strong absorption at 280 nm. Transmission electron microscopy presented a spherical shape of the prepared nanoparticles, and FTIR demonstrated different spectra for the free gallic acid sample compared to GANE. GANE showed cytotoxicity for the A549 carcinoma lung cell line with a low IC50 value. It was found that oral administration of GANE at 32.8 and 82 mg/kg.b.w. and dexamethasone (0.5 mg/kg) provided significant protection against LPS-induced pulmonary fibrosis. GANE enhanced production of superoxide dismutase, GPx, and GSH. It simultaneously reduced the MDA level. The GANE and dexamethasone, induced the production of IL-4, but suppressed TNF-α and IL-6. On the other hand, the lung p38MAPK, TGF-ß1, and NF-κB gene expression was downregulated in rats administrated with GANE when compared with the LPS-treated rats. Histological studies confirmed the effective effect of GANE as it had a lung-protective effect against LPS-induced lung fibrosis. It was noticed that GANE can inhibit oxidative stress, lipid peroxidation, and cytokines and downregulate p38MAPK, TGF-ß1, and NF-κB gene expression to suppress the proliferation and migration of lung fibrotic cells.