New 1,2,3-Triazoles from (R)-Carvone: Synthesis, DFT Mechanistic Study and In Vitro Cytotoxic Evaluation
Ali Oubella,
Abdoullah Bimoussa,
Abdellah N’ait Oussidi,
Mourad Fawzi,
Aziz Auhmani,
Hamid Morjani,
Abdelkhalek Riahi,
M’hamed Esseffar,
Carol Parish,
Moulay Youssef Ait Itto
Affiliations
Ali Oubella
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Abdoullah Bimoussa
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Abdellah N’ait Oussidi
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Mourad Fawzi
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Aziz Auhmani
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Hamid Morjani
BioSpectroscopie Translationnelle, BioSpecT—EA7506, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 Rue Cognacq Jay, CEDEX, 51096 Reims, France
Abdelkhalek Riahi
Equipe MSO, CNRS UMR 7312 Institut de Chimie Moléculaire, Université de Reims Champagne-Ardenne, Bat. Europol’Agro-Moulin de La Housse UFR Sciences B.P., 1039, CEDEX 2, 51687 Reims, France
M’hamed Esseffar
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
Carol Parish
Gottwald Science Center, 28Westhampton Way, University of Richmond, Richmond, VA 23173, USA
Moulay Youssef Ait Itto
Laboratoire de Chimie Moléculaire, Département de Chimie, Faculté des Sciences, Semlalia B.P 2390, Marrakech 40001, Morocco
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.