Synthesis and evaluation of the antiproliferative activity of new heterylmethylidene derivatives of imidazothiazolotriazinones

• Published in: New journal of chemistry 2021-07, Vol.45 (27), p.12271-12285
• Main Authors: Izmest'ev, Alexei N, Gazieva, Galina A, Anikina, Lada V, Pukhov, Sergey A, Karnoukhova, Valentina A, Kolotyrkina, Natalya G, Kravchenko, Angelina N
• Format: Article
• Language: English
• Subjects: Aldehydes; Antiproliferatives; Apoptosis; Crystallography; Hydrobromides; Leukemia; Lymphocytes; Necrosis; Synthesis
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d1nj02163j

Two novel series of 6-heterylmethylidenetetrahydroimidazo[4,5- e ]thiazolo[3,2- b ]-1,2,4-triazine-2,7(1 H ,6 H )-diones and 7-heterylmethylidenetetrahydroimidazo[4,5- e ]thiazolo[2,3- c ]-1,2,4-triazine-2,8(3 H ,7 H )-diones were synthesized by aldol condensation of tetrahydroimidazo[4,5- e ]thiazolo[3,2- b ]-1,2,4-triazine-2,7(1 H ,6 H )-dione hydrobromides with heteroaromatic aldehydes and subsequent skeletal rearrangement of the thiazolotriazine fragment. The antiproliferative activity of the synthesized compounds was evaluated. Among the derivatives, ( Z )-1,3-diethyl-7-[(1 H -indol-3-yl)methylidene]-1,3 a ,4,9 a -tetrahydroimidazo[4,5- e ]thiazolo[2,3- c ]-1,2,4-triazine-2,8(3 H ,7 H )-dione 4n exhibited the highest antiproliferative activity. The GI 50 values of the compound against 24 of the 60 cancer cell lines were < 10 nM; against 32 of the 60 cell lines, they were 11.5-63.2 nM; and the GI 50 values against the remaining 4 cell lines were 1.33-6.38 μM. Experiments with annexin showed that compound 4n induced apoptosis and necrosis in Jurkat cells (acute T cell leukemia). Two series of regioisomeric heterylmethylidene derivatives of imidazo[4,5- e ]thiazolo[3,2- b ]-1,2,4-triazines and imidazo[4,5- e ]thiazolo[2,3- c ]-1,2,4-triazines were synthesized. Several compounds exhibiting high antiproliferative activity were found.