Biopolymers and cell. 2009; 25 (6): 491 - 499

 

 

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

 

L. G. Palchykovska, I. V. Alexeeva, M. O. Platonov, O. M. Kostenko, L. S. Usenko, V. V. Negrutska, A. D. Shved

 

Institute of molecular biology and genetics NAS of Ukraine, 150, Zabolotnogo Str, Kyiv Ukraine, 03680

 

Aim. 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.

 

Keywords: 1,2,4-triazino[5,6-b][1,4]benzothiazines, design, virtual screening, synthesis, model transcription system.