A. Altharawi

Synthesis of Novel Pyrazolopyranopyrimidine Acyclic Nucleosides Disubstituted at N2/C5 as Potential Anti-SARS-CoV-2 Inhibitors: Structural Characterization, and In Silico Studies

Synthesis and in silico evaluation of novel hybrid 1,4-benzothiazine-1,1-dioxide-bis(1,2,3-triazole) derivatives as potential SRC kinase inhibitors via 1,3-dipolar cycloaddition.

Herein, we report the synthesis of new 1,4-benzothiazine-1,1-dioxide derivatives bearing bis(1,2,3-triazole) moieties via click chemistry in good to high yields and fully characterized by 1H NMR, 13C NMR and HRMS. The compounds were evaluated using a combined in silico approach, including physicochemical, pharmacokinetic and toxicity analysis, molecular docking and molecular dynamics studies. Drug-like properties of all compounds were favourable. Molecular docking against SRC kinase suggested binding affinities ranging from -7.14 to -8.13 kcal/mol. Compound 11 displayed the most favorable docking score (-8.13 kcal/mol), comparable to that of bosutinib (-8.54 kcal/mol), and formed key interactions within the active site. This finding was consistent with the 100 ns molecular dynamics simulations, which indicated that the SRC-compound 11 complex remained structurally stable and maintained key interactions with residues such as Met341, Tyr340 and Lys295. Despite showing conformational flexibility than bosutinib, compound 11 maintained stable binding throughout the simulation. Overall, compound 11 showed favorable predicted binding toward SRC kinase, suggesting that these bis-triazole derivatives may represent potential leads for future anticancer investigation.

Synthesis, molecular docking and preliminary anticancer activity of product-C as a hybrid compound against PI3K

The present work describes the synthesis, molecular docking, and preliminary anticancer evaluation of a hybrid compound, product- C composed of a fluorinated sulfur heterocyclic core and an adamantane moiety. The synthesis method was designed to tune the electronic, lipophilic and structural properties of the compound through the introduction of CF₃, F and Cl functional groups, which are well known for the improving metabolic stability, physicochemical properties and drug-likeness. The structure of the synthesized compound was confirmed by 1 H and 13 C nuclear magnetic resonance (NMR) spectra. Molecular docking against phosphoinositide 3-kinase (PI3K), a protein target implicated in multiple cancers, showed that product- C exhibited a binding affinity of -10.6 kcal/mol, suggesting favorable interaction with the target. In parallel, the SRB (Sulforhodamine B) assay was used to evaluate the cytotoxicity of product- C toward PANC-1 cells. Preliminary results showed cell viabilities of 98.86% and 95.55% after exposure to 10 μM and 100 μM of product- C , respectively. These findings indicate that product- C displays low cytotoxicity toward PANC-1 cells under the tested conditions; however, they do not by themselves demonstrate marked antiproliferative activity.