Design, Synthesis, Spectroscopic Characterisation and In Vitro Cytostatic Evaluation of Novel Bis(coumarin-1,2,3-triazolyl)benzenes and Hybrid Coumarin-1,2,3-triazolyl-aryl Derivatives

Abstract

In this work, a series of novel 1,2,3-triazolyl-coumarin hybrid systems were designed as potential antitumour agents. The structural modification of the coumarin ring was carried out by Cu(I)-catalysed Huisgen 1,3-dipolar cycloaddition of 7-azido-4-methylcoumarin and terminal aromatic alkynes to obtain 1,4-disubstituted 1,2,3-triazolyl-coumarin conjugates 2a-g, bis(1,2,3-triazolyl-coumarin)benzenes 2h-i and coumarin-1,2,3-triazolyl-benzazole hybrids 4a-b. The newly synthesised hybrid molecules were investigated for in vitro antitumour activity against five human cancer cell lines, colon carcinoma HCT116, breast carcinoma MCF-7, lung carcinoma H 460, human T-lymphocyte cells CEM, cervix carcinoma cells HeLa, as well as human dermal microvascular endothelial cells (HMEC-1). Most of these compounds showed moderate to pronounced cytotoxic activity, especially towards MCF-7 cell lines with IC₅₀ = 0.3-32 μM. In addition, compounds 2a-i and 4a-b were studied by UV-Vis absorption and fluorescence spectroscopy and their basic photophysical parameters were determined.

Keywords: 1,2,3-triazole; benzazole; coumarin; cytostatic evaluation; fluorescence; organic synthesis.

Figure 1

1,2,3-Triazolyl-coumarin-hybrids as bioactive molecules.

Figure 2

2-Thiobenzazole scaffold in bioactive molecules.

Scheme 1

Synthesis of triazolyl-coumarin conjugates 2. Reagents and conditions: (a) Method A: t-BuONO, TMSN₃, CH₃CN, rt., 2 h; Method B: p-TsOH, NaNO₂, NaN₃, rt., overnight; (b) alkyne, CuSO₄, Na ascorbate, TBTA, t-BuOH/H₂O/CH₂Cl₂, 24–72 h, 25–60 °C.

Scheme 2

Synthesis of triazolyl-coumarin conjugates 4. Reagents and conditions: (a) propargyl bromide, K₂CO₃, THF, 60 °C, 4 h; (b) CuSO₄, Na-ascorbate, t-BuOH/H₂O (1:1), rt., 24 h.

Figure 3

Concentration-response profiles for compounds 2b (a) and 2h (b) tested in vitro on human tumour cell lines HCT116, MCF-7 and H460.

Figure 4

UV-Vis absorption (a,c,e) and fluorescence emission spectra (b,d,f) of: 2a–g (a,b); 2h–2i (c,d) and 4a–b (e,f) in DMSO (c = 10 μM), λ_exc = λ_abs,max.

Figure 4

UV-Vis absorption (a,c,e) and fluorescence emission spectra (b,d,f) of: 2a–g (a,b); 2h–2i (c,d) and 4a–b (e,f) in DMSO (c = 10 μM), λ_exc = λ_abs,max.