3,6-Diazaphenothiazines as potential lead molecules – synthesis, characterization and anticancer activity

<p>3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3′-nitro-2,4′-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of <i>N</i>-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10<i>H</i>-3,6-diazaphenothiazine was 10 times more active (IC₅₀<0.72 μg/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of <i>H3</i> (proliferation marker), <i>TP53, CDKN1A</i> (cell cycle regulators)<i>, BAX</i> and <i>BCL-2</i> (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.</p

Discovery of butyrylcholinesterase inhibitors among derivatives of azaphenothiazines

<div><p></p><p>The study presents the discovery of novel butyrylcholinesterase (BuChE) inhibitors among derivatives of azaphenothiazines by application of <i>in silico</i> and <i>in vitro</i> screening methods. From an in-house library of compounds, 143 heterocyclic molecules derived from the azaphenothiazine scaffold were chosen for virtual screening. Based on results of the docking procedure, 15 compounds were identified as exhibiting the best fit for the two screening complexes (ligand – AChE and ligand – BuChE). Five compounds displayed moderate AChE and good BuChE inhibitory activity at screening concentrations of 10 µM. The IC₅₀ values for active BuChE inhibitors were in the 11.8–122.2 nM range. Three of the most active inhibitors are tetra- or pentacyclic derivatives of azaphenothiazines with the same <i>N</i>-methyl-2-piperidinethyl substituent.</p></div