The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones

  • Galina A. Gazieva
  • Alexei N. Izmest’ev
  • Lada V. Anikina
  • Sergey A. Pukhov
  • Marina E. Meshchaneva
  • Dmitry V. Khakimov
  • Natalya G. Kolotyrkina
  • Angelina N. Kravchenko
Original Article


A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations. Both imidazothiazolo[3,2-b]triazines and their rearrangement products were evaluated for their cytotoxic activity against rhabdomyosarcoma, A549, HCT116 and MCF7 human cancer cell lines by MTT assay. Among the derivatives, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3a,9,9a-tetrahydroimidazo [4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-dione 4i was found to have the highest antiproliferative activity toward the tested cell lines (4i: \(\hbox {IC}_{50} = 2.20\), 2.29, 0.47 and \(3.11\,{\upmu }\hbox {M}\), respectively). The \(\hbox {IC}_{50}\) value of compound 4i against normal human embryonic kidney cells HEK293 was \(19.34\,{\upmu }\hbox {M}\), which appeared to be 6–41-fold higher than \(\hbox {IC}_{50}\) values of 4i against human cancer cells.

Graphical Abstract


Imidazothiazolotriazine Isatin Aldol condensation Amidine rearrangement Cytotoxic activity Influence of substituents 

Supplementary material

11030_2018_9813_MOESM1_ESM.doc (1.7 mb)
Supplementary material 1 (doc 1784 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Galina A. Gazieva
    • 1
  • Alexei N. Izmest’ev
    • 1
  • Lada V. Anikina
    • 2
  • Sergey A. Pukhov
    • 2
  • Marina E. Meshchaneva
    • 1
    • 3
  • Dmitry V. Khakimov
    • 1
    • 4
  • Natalya G. Kolotyrkina
    • 1
  • Angelina N. Kravchenko
    • 1
  1. 1.N.D. Zelinsky Institute of Organic ChemistryRussian Academy of SciencesMoscowRussian Federation
  2. 2.Institute of Physiologically Active Compounds of the Russian Academy of SciencesChernogolovkaRussian Federation
  3. 3.D. Mendeleev University of Chemical Technology of RussiaMoscowRussian Federation
  4. 4.Federal State Unitary EnterpriseKeldysh Research CenterMoscowRussian Federation

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