New 1,2,4-triazine bearing compounds: molecular modelling, synthesis and biotesting

Abstract

To enlarge a spectrum of biologically active compounds in the series of the 1,2,4-triazino[5,6-b] [1,4]benzothiazine (1,2,4-TBT) derivatives and reveal among them efficient inhibitors of RNA synthesis Methods. The methods of structure optimization of the 3-oxo-1,2,4-TBT by fragment-oriented substitution, the molecular doking of new structures in a virtual target, the rational chemical synthesis of the theoretically predicted compounds and their testing in the system of transcription in vitro. Results. The series of 1,2,4-TBT derivatives with substituents in the benzene and triazine cycles of a base molecule were synthesized. The testing of synthesized compounds in the in vitro transcription system directed by T7 RNA polymerase revealed the structure-and concentration dependent inhibition of the RNA synthesis by some of these compounds. The experimental and virtual screening data for all investigated compounds have a good correlation. It was found that most effective derivative is the 3-oxo-8-butyl-1,2,4-TBT which completely inhibited transcription at the concentration of 6 mg/ml. Conclusions. The biotesting results allow us to assume that the inhibition of RNA synthesis is caused by binding of the 3-oxo-8-butyl-1,2,4-TBT to both free RNA polymerase molecules and those including in a transcriptional complex with DNA.

Synthesis and study on biological activity of nitrogen-containing heterocyclic compounds – regulators of enzymes of nucleic acid biosynthesis

“…The key non-covalent intermolecular relations of different types were determined for the ligand-receptor complex. The experimental data regarding the biological activity of the synthesized compounds are in sufficient agreement with the results of virtual screening [21].…”

“…Another way is the formation of tricyclic heterobase with fixed location of the sugar residue, taking into account corresponding triazine nucleosides, where the heterocycle is finished completely. This was the way to confirm the region-specificity of the glycosylation reaction as well as to reveal the dependence of the synthesis efficiency on the nature of benzene ring substitutes (method 1) or the substitutes of ortho-aminothiophenol -the initial compound in the annelation reaction (method 2) [20][21].…”

“…The department performed a considerable cycle of works [20][21][22][23] on the synthesis and investigation of derivatives of 3-oxo-1,2,4-triazine[5,6-b] [1,4]benzothiazine (3-oxo-1,2,4-TBT; 6) -the structural analogues of triazine-containing polycyclic antibiotics. In part we changed the procedure of searching for potential inhibitors of T7pol using the molecular docking method and started computational investigation in determining the topology and tautomeric status of the main compound -3-oxo-1,2,4-TBT.…”

Inhibition of in vitro transcription by 2-arylidene derivatives of thiazolo[3,2-α]benzimidazol-3(2H)-one

“…T7 RNAP is thus a reliable in vitro model used for the studies of transcription [3][4][5][6] and mechanism of action of DNAbinding drugs [7][8][9][10]. This system was proposed in our previous papers for the screening of nucleic acids synthesis inhibitors [11][12][13].…”

Evaluation of antibacterial and antiviral activity of N-arylamides of 9-methyl and 9-methoxyphenazine-1-carboxylic acids – inhibitors of the phage T7 model transctiption

“…Therefore, we selected an easy-to-use and productive transcription system on the basis of DNAdependent RNA-polymerase of phage T7 (RNAP T7) for the purpose of screening synthesized compounds and selecting RNA synthesis inhibitors. This model system was successfully used to reveal efficient inhibitors of transcription -antimicrobial and/or antiviral agents [18][19][20]. The preliminary testing of arylamides of 9-substituted PCA-1 in the abovementioned model system demonstrated reliable inhibition of RNA synthesis by a number of compounds at the concentration of 25 µg/ml (~80 µM) [11].…”