New 1,2,3-Triazoles from (R)-Carvone: Synthesis, DFT Mechanistic Study and In Vitro Cytotoxic Evaluation

Abstract

Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide-alkyne cycloaddition reaction using CuSO₄,5H₂O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a-h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC₅₀ values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC₅₀ value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

Keywords: (R)-carvone; 1,2,3-triazole; DFT calculations; cytotoxic activity; regioselectivity.

Scheme 1

Potential anticancer drugs based on 1,2,3-triazole nucleus.

Scheme 2

Synthetic route for the preparation of terminal alkyne 7.

Scheme 3

The obtainable heterocyclic systems from CuAAC reaction of 7 with aromatic azides 8a–h.

Scheme 4

General schematic for the synthesis of novel 1-4-disubstituted 1,2,3-triazoles 9a–h.

Figure 1

The HMBC correlations of 9a.

Scheme 5

Activation energies in terms of Gibbs free energies (kcal/mol) of all the transition states associated with the corresponding regioisomers of the uncatalyzed 32CA reaction of 7 and 8a. The energy reference is the separated reagents(values in kcal/mol).

Scheme 6

Optimized geometries of the regioisomericTS-1 and TS-2 associated with the uncatalyzed 1,3-dipolar cycloaddition reaction of 7 and 8a. The distances are given in Å.

Scheme 7

Thermaland copper-catalyzed cycloaddition reaction of azides and alkynes.

Figure 2

Mechanistic profiles of the regioisomeric approaches of 8a and 2Cu(I)-7. (Bold numbers for gas phase and numbers between brackets for ethanol as reaction medium).

Scheme 8

Optimized geometries of the stationary points in the 2Cu(I) catalyzed 32CA reaction. The lengths are given in Å.