Design, Synthesis and Antibacterial Activity of Coumarin-1,2,3-triazole Hybrids Obtained from Natural Furocoumarin Peucedanin

Abstract

Synthesis of 1,2,3-triazole-substituted coumarins and also 1,2,3-triazolyl or 1,2,3-triazolylalk-1-inyl-linked coumarin-2,3-furocoumarin hybrids was performed by employing the cross-coupling and copper catalyzed azide-alkyne cycloaddition reaction approaches. The synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Bacillius subtilis, Actinomyces viscosus and Escherichia coli bacterial strains. Coumarin-benzoic acid hybrids 4с, 42с and 3-((4-acetylamino-3-(methoxycarbonyl)phenyl)ethynyl)coumarin (29) showed promising activity against S. aureus strains, and the 1,2,3-triazolyloct-1-inyl linked coumarin-2,3-furocoumarin hybrid 37c was endowed with high selectivity against B. subtilis and E. coli species. The in vitro antibacterial activity of 4с, 29, 37c and 42с can potentially be compared with that of a number of modern antibiotic drugs used in the clinic, suggesting promising prospects for further research. A detailed study of the molecular interactions with the targeted protein MurB was performed using docking simulations and the obtained results are quite promising.

Keywords: CuAAC reaction; Sonogashira coupling; antibacterial activity; coumarin; furocoumarin.

Figure 1

Chemical structures of coumarin-1,2,3-triazole hybrids of types A–D.

Scheme 1

Synthesis 6-(1-(carboxyphenyl)-1H-1,2,3-triazol-4-ylcarbamoyl)umbelliferones 4a–c. Reagents and Conditions: (a) 20% eq. NaOH, dioxane, reflux, 20 min; (b) DCC, HOBt, Et₃N, DMF, rt, 48 h; (c) CuSO₄^.5H₂O (5 mol%), sodium ascorbate (15 mol%), H₂O-CH₂Cl₂, 20→40 °C.

Scheme 2

Synthesis of 3-(triazolyl)-substituted coumarins 8–10. Reagents and Conditions: (a): dioxane dibromide, CH₂Cl₂, rt, 16 h; (b): NaN₃, DMF, 40 °C, 14 h; (c) CuSO₄, sodium ascorbate, eq. CH₂Cl₂ (1:1), rt, 3 h, then 40 °С, 1 h; (d): CuI, Et₃N, MeCN, rt, 10 h.

Scheme 3

Synthesis 3-arylethynylcoumarins 17, 24–29, 3-(alkynyl)coumarins 31, 33, and 3-(ethynyl)peuruthenicin (34). Reagents and Conditions: (a): Pd(PPh₃)₂Cl₂, CuI, Et₃N, benzol, 110 °C, 12 h; (b) Pd(PPh₃)₂Cl₂, CuI, Et₃N, Bu₄NBr, DMF; (c) Pd(PPh₃)₂Cl₂, CuI, Et3N, toluene, MAOS, 100 °C, 2 h; (d) CsF, MeOH, TEBA, rt, 10 h.

Scheme 4

Synthesis of coumarin-2,3-dihydrofurocoumarin hybrids linked with 1H-1,2,3-triazole rings. Reagents and Conditions: (a): CuSO₄^.5H₂O (5 mol%), sodium ascorbate (15 mol%), H₂O-CH₂Cl₂, 20→40 °C; (b): CuSO₄^.5H₂O, sodium ascorbate, H₂O-CH₂Cl₂, 40 °C, 5 h; (c) Pd(PPh₃)₂Cl₂, CuI, Et₃N, benzene, 80 °C, 14 h.

Figure 2

Chemical structures of antibacterial coumarin-benzoic acid hybrids and coumarin-furocoumarin hybrids with a 1,2,3-triazolyl linker.

Figure 3

Noncovalent interactions of compounds (3A—4c, 3B—42c, 3C—37c, 3D—FAD) are shown by dotted lines: green—hydrogen bonds, purple—stacking interactions, orange—electrostatic interactions. Hydrophobic interactions and nonpolar hydrogens are omitted. (A) 3D interactions of ligand 4c at the FAD binding site of MurB Protein. (B) 3D interactions of ligand 42c at the FAD binding site of MurB Protein. (C) 3D interactions of ligand 37c at the FAD binding site of MurB Protein. (D) 3D interactions of FAD molecule at the binding site of MurB Protein.

Figure 3

Noncovalent interactions of compounds (3A—4c, 3B—42c, 3C—37c, 3D—FAD) are shown by dotted lines: green—hydrogen bonds, purple—stacking interactions, orange—electrostatic interactions. Hydrophobic interactions and nonpolar hydrogens are omitted. (A) 3D interactions of ligand 4c at the FAD binding site of MurB Protein. (B) 3D interactions of ligand 42c at the FAD binding site of MurB Protein. (C) 3D interactions of ligand 37c at the FAD binding site of MurB Protein. (D) 3D interactions of FAD molecule at the binding site of MurB Protein.