The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones

Abstract

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: [Formula: see text], 2.29, 0.47 and [Formula: see text], respectively). The [Formula: see text] value of compound 4i against normal human embryonic kidney cells HEK293 was [Formula: see text], which appeared to be 6-41-fold higher than [Formula: see text] values of 4i against human cancer cells.

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

“…The reaction of 5,7-dimethylimidazo[4,5-e]triazine-3-thione (3a) with DEAD proceeded in alcohols with moderate regioselectivity and isomer 5 predominated in the filtered precipitates (Table 1, entries 1-3). The use of absolute or 95% ethanol as a solvent did not significantly affect the total yields of isomers 4 and 5 and their ratio, while carrying out the reaction in acetic acid, as expected [13,23,24], led to a change in regioselectivity and the formation of linear isomer 4 as the main product (Table 1, entries 4-6). 5,7-Diethylimidazo[4,5-e]triazine-3-thione (3b) reacted with DEAD in a similar manner (Table 1, entries 7 and 8), but with less selectivity.…”

“…The structures of compounds 4a-n and 5a-n were elucidated by IR, 1 H and 13 C NMR, and HRMS spectral data. There are downfield shifts of the NH group proton signal from 6.9-7.2 to 8.0-8.4 ppm in the 1 H NMR spectra of angular structures 5 in comparison to the spectra of the linear isomers 4.…”

“…A significant number of biologically active thiazolidines amount to their heteroannelated derivatives, namely, condensed thiazolo [3,2-a]pyrimidines [9] and thiazolo [3,2-b]-1,2,4-triazoles [10], as well as related thiazolo [3,2-b]-1,2,4-triazines and thiazolo [2,3-c]-1,2,4-triazines possessing antimicrobial, antidepressant, anti-HIV, and anticancer activities [10][11][12][13][14][15]. Modifications of the position 5 of the thiazolidine cycle often lead to an enhancement of the pharmacological properties of the resulting products, which have received considerable attention in reviews [16,17].…”

Recent updates on 1,2,3‐, 1,2,4‐, and 1,3,5‐triazine hybrids (2017–present): The anticancer activity, structure–activity relationships, and mechanisms of action

“…The tetrahydroimidazo[4,5‐ e ]thiazolo[3,2‐ b ][1,2,4]triazine‐2,7(1 H ,6 H )‐dione 12 (IC 50 : 0.47–3.11 µM, MTT assay) was 2.0–26.2 folds more potent than amptothecin (IC 50 : 4.49–13.62 µM) against HCT‐116 (most sensitive cancer cells, IC 50 : 0.47 µM), MCF‐7, RD, and A549 cancer cell lines. [ 37,38 ] Moreover, hybrid 12 (IC 50 : 19.34 µM) also displayed acceptable cytotoxicity toward normal HEK293 cells and exerted antiproliferative activity by inducing apoptosis.…”

“…lines. [37,38] Moreover, hybrid 12 (IC 50 : 19.34 µM) also displayed acceptable cytotoxicity toward normal HEK293 cells and exerted antiproliferative activity by inducing apoptosis.…”