Microwave assisted synthesis of some new fused 1,2,4-triazines bearing thiophene moieties with expected pharmacological activity

Abstract

Rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4H)-one 1 under microwave irradiation is described. Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b][1,3,4]thiadiazinones, 1,3,4-thiadiazolo[2,3-c][1,2,4]triazinone and pyrazolo[5,1-c]-[1,2,4]triazine-7-carbonitrile, have been synthesized by treatment of 1 with bifunctional oxygen and halogen compounds, CS₂/KOH and malononitrile via heterocyclization reactions, in addition to some uncondensed triazines. Structures of the products have been deduced from their elemental analysis and spectral data (IR, ¹H-NMR, ¹³C-NMR). Select new synthesized compounds were screened as anticancer agents, with some showing activity as cytotoxic agents against different cancer cell lines.

Scheme 1

Microwave synthesis of compound 1.

Scheme 2

Syntheses of compounds 3-8.

Scheme 3

Synthesis of compounds 9-15.

Figure 1

Cytotoxicity (IC50, µg/mL) of different tested compounds against human Hep-G2 cells 48 hours of incubation. The grey bars represent non-cytotoxic compounds, and the black bars represent the promising cytotoxic compounds. Data are representing mean value of IC50 ± SE.

Figure 2

Cytotoxicity (IC₅₀, µg/mL) of different tested compounds against human MCF-7 cells 48 hours of incubation. The grey bars represent non-cytotoxic compounds, and the black bars represent the promising cytotoxic compounds. Data are representing mean value of IC₅₀ ± SE.

Figure 3

Cytotoxicity (IC50, µg/mL) of different tested compounds against human HCT-116 cells 48 hours of incubation. The grey bars represent non-cytotoxic compounds, and the black bars represent the promising cytotoxic compounds. Data are representing mean value of IC50 ± SE.

Figure 4

The type of cell death was investigated in Hep-G2 cells after the treatment with the promising cytotoxic compounds, using acridine orange/ethidium bromide staining to compare between the percentage of necrotic cells (grey segment) and the apoptotic cells (black segment). Data are representing mean value ± SE.

Figure 5

The type of cell death was investigated in MCF-7 cells after the treatment with the promising cytotoxic compounds, using acridine orange/ethidium bromide staining to compare between the percentage of necrotic cells (grey segment) and the apoptotic cells (black segment). Data are representing mean value ± SE.

Figure 6

The type of cell death was investigated in HCT-116 cells after the treatment with the promising cytotoxic compounds, using acridine orange/ethidium bromide staining to compare between the percentage of necrotic cells (grey segment) and the apoptotic cells (black segment). Data are representing mean value ± SE.