Recognition of arylmethylidene derivatives of imidazothiazolotriazinones as novel tubulin polymerization inhibitors.

Two series of arylmethylidene derivatives of imidazothiazolotriazinone differing in the structure of the imidazothiazolotriazine fragment were synthesized and their antiproliferative activity and effect on tubulin polymerization were evaluated. Some of the synthesized derivatives showed a significant antiproliferative effect, among which (Z)-7-(2,4-dichlorobenzylidene)-1,3-diethyl-1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-2,8(3H,7H)-dione 2n exhibited the highest antiproliferative activity. The GI50 values of the compound against 56 of the 58 cell lines were 19.4-87.8 nM; against the remaining 2 cell lines, they were 0.544-1.29 µM. Moreover, further mechanism analysis demonstrated that 2n caused G2/M arrest, induced cell apoptosis in K562 cells and blocked tubulin polymerization in the same way as colchicine.

Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium.

Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4' atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component.

Synthesis of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines via a base-induced rearrangement of functionalized imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazines.

A series of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines was synthesized via a cascade sequence of hydrolysis and skeletal rearrangement of imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazin-7(8H)-ylidene)acetic acid esters in methanol upon treatment with excess KOH. Imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazin-6(7H)-ylidene)acetic acid esters are also suitable substrates for the reaction. In this case hydrolysis and thiazole ring expansion were accompanied with the change of the thiazolotriazine junction type from thiazolo[3,2-b][1,2,4]triazine to thiazino[2,3-c][1,2,4]triazine.

Synthesis and Evaluation on the Fungicidal Activity of S-Alkyl Substituted Thioglycolurils.

A series of S-alkyl substituted thioglycolurils was prepared through the alkylation of corresponding thioglycolurils with halogenoalkanes and tested for their fungicidal activity against six phytopathogenic fungi from different taxonomic classes: Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum, and two pathogenic yeasts: Candida albicans and Cryptococcus neoformans var. grubii. A number of S-alkyl substituted thioglycolurils exhibited high activity against Venturia inaequalis and Rhizoctonia solani (85-100% mycelium growth inhibition), and moderate activity against other phytopathogens. S-Ethyl substituted thioglycolurils possessed a high activity against Candida albicans. Additionally, the hemolytic and cytotoxic properties of promising derivatives were determined using human red blood cells and human embryonic kidney cells, respectively. Two S-ethyl derivatives possessed both low cytotoxicity against normal human cells and high fungicidal activity against Candida albicans.

A new reversible transformation of oxindolylidene derivatives of imidazothiazolotriazine into 3-[(imidazotriazin-3-yl)thio]-2-oxoquinoline-4-carboxylates.

A simple method for the synthesis of water-soluble potassium 3-[(imidazotriazin-3-yl)thio]-2-oxoquinoline-4-carboxylates was developed based on a new reversible transformation of oxindolylidene derivatives of imidazothiazolotriazine that results from their treatment with potassium hydroxide. The antiproliferative activity of the synthesized compounds was evaluated against 58 cell lines and compared with oxindolylidene derivatives of imidazothiazolotriazine. Quinoline derivatives 3 demonstrated high activity with average GI50 values of <10 µM which are comparable or higher than those of the oxindolylidene imidazothiazolotriazines. Compound 3a, with a pent-3-yl substituent at the nitrogen atom of the quinoline fragment, possessed the highest antiproliferative activity with an average GI50 value of 1.71 µM. The GI50 values of compound 3a against 52 of the 58 cell lines were <1 µM; against the remaining 6 of the 58 cell lines, they were in the range 1.21-39.2 µM.

Synthesis, Structure and Stereochemistry of Dispirocompounds Based on Imidazothiazolotriazine and Pyrrolidineoxindole.

Methods for the synthesis of two types of isomeric dispirocompounds based on imidazothiazolotriazine and pyrrolidineoxindole, differing in the structure of imidazothiazolotriazine fragment, namely, linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine- 4',3″-indolines] and angular dispiro[imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine-7,3'-pyrrolidine-4',3″-indolines] were proposed. The first method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from paraformaldehyde and N-alkylglycine derivatives to the corresponding oxindolylidene derivatives of imidazothiazolotriazine. The cycloaddition leads to a mixture of two diastereomers resulted from anti- and syn-approaches of azomethine ylide in approximately a 1:1 ratio, which were separated by column chromatography. Another method consists in rearrangement of linear dispiro[imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3'-pyrrolidine-4',3″-indolines] into hitherto unavailable angular dispiro[imidazo[4,5-e]thiazolo[2,3-c]-[1,2,4]triazine-7,3'-pyrrolidine-4',3″-indolines] upon treatment with KOH. It was found that the anti-diastereomer of linear type underwent rearrangement into the isomeric angular syn-diastereomer, while the rearrangement of the linear syn-diastereomer gave the angular anti-diastereomer.

Synthesis and antiproliferative activity characterization of new imidazothiazolotriazine oxindolylidene derivatives containing various substituents in the oxindole ring.

Condensation of 1,3-diethyltetrahydroimidazo[4,5-е]thiazolo[3,2-b][1,2,4]triazine-2,7-dione with isatins followed by framework rearrangement in the thiazolotriazine moiety was used to synthesize two new series of oxindolylidenetetrahydroimidazo[4,5-е]thiazolo- [3,2-b][1,2,4]triazine-2,7-diones and oxindolylidenetetrahydroimidazo[4,5-е]thiazolo[2,3-c][1,2,4]triazine-2,8-diones containing various substituents in the oxindole moiety. The obtained compounds were tested for antiproliferative activity. The greatest activity was observed in the case of 1-alkyl-7-methyloxindolylidene derivatives of imidazo[4,5-е]thiazolo[2,3-c]triazine, which not only inhibited the growth of more than half of the studied cell lines, but also caused cell death in the SF-539 cell line (central nervous system cancer, mean growth percent -7.82%) and MDA-MB-435 (melanoma, -30.97 and -13.64%). Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-022-03125-3.

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.

Two series of functionalized imidazothiazolotriazine derivatives were synthesized via the condensation of imidazo[4,5-e]-1,2,4-triazine-3-thiones with acetylenedicarboxylic acid dimethyl and diethyl esters (DMAD and DEAD) and subsequent base-catalyzed rearrangement of the obtained imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazines into regioisomeric imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine derivatives.

Dimroth-type N/S-interchange of N-aminothioglycolurils in the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolones.

An original method for the synthesis of 2-hydrazonoimidazo[4,5-d]thiazolone derivatives has been developed based on a one-pot acid-induced sequence of hydrazone formation from 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazinones and aromatic aldehydes, triazine ring contraction to imidazolidine one, and Dimroth-type N/S-interchange of N-aminothioglycolurils formed in situ into 2-hydrazonoimidazo[4,5-d]thiazolones. 3-Phenylacroleine derivatives are also suitable substrates for the reaction with thioxoperhydroimidazotriazinones.

Diastereodivergent synthesis of dispiroheterocyclic structures comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties.

Highly diastereoselective methods for the synthesis of two different diastereomers of polynuclear dispiroheterocyclic compounds with five chiral centers comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties (dispiro[imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-7,3'-pyrrolidine-2',3''-indoles]) have been developed on the basis of a dipolar cycloaddition of azomethine ylides to benzylidene derivatives of imidazothiazolotriazines and an alkali-induced rearrangement of the thiazolotriazine fragment. The different sequence of the cycloaddition and rearrangement stages allows us to perform the targeted synthesis of two diastereomerically pure products from the same starting compounds.

The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones.

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 and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.

A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in vitro. Among the derivatives, 4-((E)-((E)-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116 cell lines (8i: IC50 = 0.02 and 0.012 µM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-((E)-((E)-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549 cells (8l: IC50 = 0.61 µM) compared to reference drugs. The IC50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 µM, respectively, exceeding the IC50 values of this compound toward the RD, HCT116 (8i) and A549 cells (8l) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R. solani, F. oxysporum, and F. moniliforme exceeding those of triadimefon.

Substituted N-aminothioglycolurils containing thiosemicarbazone moiety and their cytotoxic activity in vitro.

A library of hybrid molecules bearing thioglycoluril and (hetero)aromatic aldehyde thiosemicarbazone moieties was synthesized via a tandem hydrazone formation-ring contraction reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (hetero)aromatic aldehydes. All synthesized compounds were tested for their cytotoxic activity against rhabdomyosarcoma, A549, and MS human cancer cell lines by MTT-assay. Among the derivatives, (E)-4-benzylideneamino-1,3-dimethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one 1f was found to have the most marked antiproliferative activity toward the tested cell lines (1f: IC[Formula: see text] 23.7, and 6.4 [Formula: see text]M, respectively). The IC[Formula: see text] value of thioglycoluril 1f against normal human embryonic kidney cells HEK293 was 72.5 [Formula: see text]M, which appeared to be 3-11-fold higher than IC[Formula: see text] values of 1f against human cancer cells.

An effective one-pot access to polynuclear dispiroheterocyclic structures comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties via a 1,3-dipolar cycloaddition strategy.

An effective and highly regio- and diastereoselective one-pot method for the synthesis of new polynuclear dispiroheterocyclic systems with five stereogenic centers (dispiro[imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-6,3'-pyrrolidine-2',3''-indoles]) comprising pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine moieties has been developed. The method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin derivatives and sarcosine to 6-benzylideneimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7-diones.