Synthesis of novel 1,2,3-triazole-based hybrids via click reactions

1,2,3-Triazoles have attracted the interest of researchers due to their wide range of biological activities which include antitumor, anti-leishmanial, bioluminescent and fungicidal activities This paper describes the synthesis of novel triazole hybrids containing biologically active fragments through cycloaddition (click) reactions, with the aim of increasing the diversity of known and active 1,2,3-triazole derivatives. All new compounds have been characterized by physicochemical methods.


Introduction
Since many drugs used in medical therapy contain heterocycles in their structure, the introduction in their structure of triazole rings, especially 1,2,3-triazoles, has attracted special attention.The syntheses and the behavior of these heterocyclic compounds have been intensely investigated in the last decades -research into the development of new methods for the synthesis of substituted triazoles and identification of their possible biological/pharmacological properties thus proceed with great interest.In fact, several new methods for producing various 1,2,3-triazole derivatives 1,2 have been recently proposed, and it has been shown that the novel compounds derived through this approach have a wide spectrum of biological properties/activities.Among these bioactivities, cytotoxic, 3 antitumor, 4 leishmanicidal, 5 bioluminescent 6 and fungicidal 7 activities should be noted, all which have been shown to be characteristic of certain 1,2,3-triazoles.The analysis of literature data shows that the nature of substituents on the triazole cycle is very important.Thus, modification of these substituents is expected to result in significant changes in the biological properties of 1,2,3-triazole 44derivatives thus formed.For this reason, research into the development of methods for the synthesis of novel substituted triazoles is constantly increasing. 8,9Of particular value are studies on the isolation and investigation of substances from natural raw materials that possess cytotoxic, 10 antitumor 11 activities, or being inhibitors of topoisomerase, 12 DPP-4 and cancer cell growth. 135][16] In this paper we propose the synthesis of novel triazole-linked hybrids containing biologically active fragments, with the aim to increase the structural range of known and active 1,2,3-triazole derivatives.

Conclusions
In summary, we synthesized new 1,2,3-triazole based hybrids with possible interesting biological/pharmacological activities by the Cu-catalyzed click reaction between synthesized alkynes and azides, containing novel chemical frameworks potentially responsible for interesting biological activities.These bioactivities will be ascertained in ongoing studies and will be reported in due course.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded in DMSO/CCl4 (1/3) solution (300 MHz for 1 H and 75 MHz for 13 C, respectively) on a Varian Mercury 300VX spectrometer.Chemical shifts were reported as δ (parts per million) relative to TMS as internal standard.IR spectra were recorded on Nicolet Avatar 330-FT-IR spectrophotometer and the reported wave numbers were given in cm −1 .All melting points were determined in an open capillary and were uncorrected.Elemental analyses were performed on a Elemental Analyzer Euro EA 3000.Compounds 2, 27 5, 32 6, 23,24 9, 33,34 11 35 were already described.

General procedure for the synthesis of azido-lactones (3a,b).
To the corresponding bromomethyl-lactone 2 (1 mmol) in DMSO (5 mL) NaN3 (1.35 mmol, 0.088 g) was added and the mixture was stirred for 12 h at room temperature.After the reaction mixture was poured in water (60 mL) and extracted with DCM (315 mL).Combined extracts were dried over Na2SO4, volatiles were evaporated and the residue was passed through a short silica gel pad in hexane-DCM 1:1 to obtain pure product.

General procedure for the synthesis of 3(6)-(4-chloroacetylpiperazin-1-yl)pyridines (7).
To a stirred solution of compound 6 (5 mmol) and pyridine (6 mmol) in absolute benzene (75 mL) the chloroacetyl chloride (4.8 mL, 6 mmol) was added dropwise.The reaction mixture was maintained at 35 o C for 6 h.After cooling of the reaction mixture at room temperature, the solvent was removed under vacuum and water (50 mL) was added.The resulting crystals were filtered off, washed with water, dried and recrystallized from ethanol.

General procedure for the synthesis of 3(6)-(4-azidoacetylpiperazin-1-yl)pyridines (8).
A mixture of compound 7 (5 mmol) and sodium azide (0.36 g, 5.5 mmol) in acetone (30 mL) was refluxed for 15 h.After the filtration the solvent was removed under vacuum and water (50 mL) was added.The resulting crystals were filtered off, washed with water, dried, and recrystallized from ethanol.

General procedure for the synthesis of propargyl-derivatives (10a-e and 12a,b).
To a stirred suspension of compound 9 (11) (5 mmol) and potassium carbonate (0.76 g, 5.5 mmol) in absolute DMF (30 mL) the propargyl bromide (5.5 mmol) was added dropwise.The reaction mixture was maintained at 50-60 o C for 5 h.Then the reaction mixture was cooled at room temperature, and water was added (50 mL).The resulting crystals were filtered off, washed with water, dried and recrystallized from ethanol.