Biopolym. Cell. 2009; 25(6):491-499.
Bioorganic Chemistry
New 1,2,4-triazine bearing compounds: molecular modelling, synthesis and biotesting
1Palchykovska L. G., 1Alexeeva I. V., 1Platonov M. O., 1Kostenko O. M., 1Usenko L. S., 1Negrutska V. V., 1Shved A. D.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


Aim. The addition of the new biologically active compounds to the series of the 1,2,4-triazino[5,6-b] [1,4]benzothiazine (1,2,4-TBT) derivatives and reveal among them the RNA synthesis inhibitors. Methods. The methods of structure optimization the 3-oxo-1,2,4-TBT by fragment-oriented substitution, the molecular doking of the new structures in a virtual target, the rational chemical synthesis of the theoretically prognoses compounds and their testing in the model transcription in vitro. Results. The series of 1,2,4-TBT derivatives with substituents in the benzene and triazine cycles of the base molecule were synthesized. Testing of the synthesized compounds in in vitro transcription system directed by T7 RNA polymerase revealed the structure- and concentration-dependent inhibition of the RNA synthesis by some of 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. Analysis of the testing data allows us to assume that the inhibition of the RNA synthesis is caused by binding of the 3-oxo-8-butyl-1,2,4-TBT both as to free RNA polymerase molecules, as to those consisting in transcriptional complex with DNA.
Keywords: 1,2,4-triazino[5,6-b][1,4]benzothiazines, design, virtual screening, synthesis, model transcription system


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