A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC 50 values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.

In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1–4) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC50) and SARS-CoV-2 inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC50 values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

Sphingosine kinase enzymes (SK1 and SK2) catalyse the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding 'J-channel' in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency. -phosphate (S1P) is a key signalling lipid derived from sphingosine (Sph) by the action of sphingosine kinases (SK1 and SK2). S1P is transported to the extracellular environment, where it functions as a ligand for a family of five S1P-specific G protein coupled receptors (S1P 1-5 ), but it also acts on specific intracellular target proteins, such as histone deacetylases 1/2 (HDAC1/2). 1, 2 Irreversible cleavage of S1P is catalysed by S1P lyase, producing (E)-2hexadecenal and phosphoethanolamine, 3 but S1P is also reversibly dephosphorylated by S1P phosphatase to regenerate Sph, 4-6 levels of which are additionally influenced by flux through the ceramide (Cer) synthesis pathway. 7 The effects of S1P on cell function favour proliferation, migration, differentiation and survival and are generally opposed by Cer, which induces apoptosis, senescence and growth arrest. 8,9 As a consequence the concept of the 'sphingolipid rheostat' was proposed, 10,11 in which the inter-conversion of Cer via Sph to S1P controls cellular fate (recently reviewed 12,13 ). Altered S1P signalling has been associated with numerous pathophysiologies, including cancer, cardiovascular disease, neurodegenerative conditions, diabetes and inflammatory disease. 14 The possibility of manipulating the sphingolipid rheostat for therapeutic purposes has therefore provided a rationale for exploring the development of SK inhibitors and their potential to reduce S1P formation and signalling and to raise pro-apoptotic Cer levels.The SK1 and SK2 enzymes are encoded by distinct genes and differ in their subcellular localisation, biochemical properties and functions; there are three N-terminal variants of SK1 and two N-terminal variants of SK2. 15,16 A number of classes of SK inhibitors have emerged in the last two decades, including the recent discovery of an ATP-competitive SK inhibitor chemotype that decreases cellular S1P levels, elevates Sph/Cer, induces apoptosis, and that inhibits cell proliferation and colony formation. 17 Most work to date, however, has focused on the development Sph-competitive inhibitors. This includes the development of inhibitors selective for SK1 t...

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).