Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1–3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1–2.8) with azaheterocycles. Alternatively, compounds 3.1–3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1–1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by 1H, 13C NMR, LC–MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI50 < −5.65). The “structure-activity” relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.
in Wiley Online Library (wileyonlinelibrary.com).Synthesis of 1-methyl-6-((2-(aryl-(heteryl-))-2-oxoethyl) pteridine-2,4,7(1H,3H,8H)-triones via [4 + 2]-cycloaddition of 1-methyl-5,6-diaminouracil with ethyl 4-aryl(heteryl)-2,4-dioxobutanoates is described in presented work. It was established that the reaction occurs regioselectively and proceeds under refluxing of starting compounds in acetic acid for 60 min. The structures of synthesized compounds were proven by complex of physicochemical methods including infrared, 1 H-, 13 C-NMR spectroscopy, liquid chromatographymass spectrometry, and electron impact-mass spectrometry. Based on the detail analysis of the correlational NMR spectral data (correlation spectroscopy, heteronuclear single quantum coherence, heteronuclear multiple bond correlation, and Nuclear Overhauser effect spectroscopy), it was determined that in dimethyl sulfoxide solution, the 1-methyl-6-((2-(aryl-(heteryl-))-2-oxoethyl)pteridine-2,4,7(1H,3H,8H)-triones exist in two tautomeric forms: ketone (A) and enol (B). It was also found that tautomeric behavior of aforementioned compounds in hexadeuterated dimethyl sulfoxide is sensitive to the nature of the aryl or heteryl substituent at the position 6 of ring. The electron donating groups shift equilibrium to the tautomer A, while electron withdrawingto the tautomer B. The synthesized compounds were tested on antiradical activity. It was found that obtained compounds reveal radical scavenging activity comparable or higher than ascorbic acid.
The series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with thiazole and thiadiazole fragments in a molecule were obtained by alkylation of potassium salts 1.1–1.4 by N-hetaryl-2-chloroacetamides and by aminolysis of activated acids 2.1–2.4 with N,N’-carbonyldiimidazole (CDI). The structures of compounds were determined by IR, 1H NMR, MS, and EI-MS analysis. The results of cytotoxicity evaluated by the bioluminescence inhibition of bacterium Photobacterium leiognathi, Sh1 showed that the compounds have considerable cytotoxicity. The synthesized compounds were tested for anticancer activity in NCI against 60 cell lines. Among the highly active compounds 3.1, 3.2, and 6.5, 2-[(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]-N-(1,3-thiazol-2-yl)acetamide (3.1) was found to be the most active anticancer agent against the cell lines of colon cancer (GI50 at 0.41–0.69 μM), melanoma (GI50 0.48–13.50 μM), and ovarian cancer (GI50 0.25–5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.
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