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

Abstract

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.

Design, synthesis andin vitroevaluation of the hybrids of oxindolylidene and imidazothiazolotriazine as efficient antiproliferative agents

“…In the 1 H NMR spectra of products 1a–w and 5a–z , a strong downfield shift of the indole H-4′ proton signals (8.79–8.89 and 8.26–8.86 ppm, respectively) was observed, which is characteristic of proximity of the carbonyl group C(7)O or C(8)O. 5,6 The homogeneity of compounds 1f–h , 1j , 1k , 1n , 1p , 1r , 1u–w and 5b , 5e , 5f , 5h , 5k , 5p , 5r , 5x–z was confirmed by powder X-ray diffraction. The results of the analysis of the experimental powder diffraction patterns of the compounds 1f–h , 1j , 1k , 1n , 1p , 1r , 1u–w and 5b , 5e , 5f , 5h , 5k , 5p , 5r , 5x–z showed that the investigated samples were single-phase.…”

“…Oxindolylidene derivatives of imidazothiazolotriazines were synthesized according to earlier 5 b elaborated methods via condensation of imidazothiazolotriazine hydrobromides with isatin or N -alkylisatins prepared by alkylation of unsubstituted isatin with the corresponding alkylhalogenides. The linear structures 1a–w were formed in boiling methanol in the presence of 1.07 equiv.…”

“…A general method for the preparation of starting compounds 3a–d has been previously reported. 5 d ,8…”

“…Earlier, 5 we had synthesized ylidene substituted imidazo[4,5- e ]thiazolo[3,2- b ]- or imidazo[4,5- e ]thiazolo[2,3- c ]-1,2,4-triazines and studied their antiproliferative activity. It was found that oxindolylidene and heteroarylmetylidene derivatives of imidazothiazolotriazines possess high antiproliferative activity (Fig.…”

“…Based on the data obtained, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3 a ,9,9 a -tetrahydroimidazo[4,5- e ]thiazolo[3,2- b ]-1,2,4-triazine-2,7(1 H ,6 H )-dione 1d was found to have the highest antiproliferative activity toward the tested cell lines among the oxindolylidene derivatives. 5 d Investigation of antiproliferative properties of heteroarylmetylidene derivatives of imidazothiazolotriazines against 60 cancer cell lines revealed apart from the main regularities described for oxindole containing compounds one more regularity – that imidazo[4,5- e ]thiazolo[2,3- c ]-1,2,4-triazine derivatives are more active compared to imidazo[4,5- e ]thiazolo[3,2- b ]-1,2,4-triazines. Amidst the heteroarylmetylidene derivatives, compound 2 was found to be a lead compound.…”