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.

Synthesis and Biological Evaluation of Novel Thiazole Analogs with Both Anti‐Proliferative and Mechanistic Analyses and Molecular Docking Studies

“…The cytotoxic activity was evaluated using the MTT assay. [39][40][41][42][43] Doxorubicin (DOX) was used as a positive, and the IC 50 values are presented in Table 1.…”

Novel isoxazoline‐linked 1,3,4‐thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation

“…[35] Similarly, a set of isoxazoline derivatives (compound 5 as an example) have been developed and investigated for their biological properties by Chaitanya et al They demonstrated that such compounds were able to induce apoptosis through DNA strand breaks and PARP1 cleavage. [36] According to these findings and to continue our efforts to discover other derivatives of monoterpenes and nucleoside analogs, which could also have interesting biological properties, [37][38][39][40] we report here the synthesis of new heterocyclic system hybrids incorporating isoxazoline and 1,3,4-thiadiazole, using 1,3-dipolar cycloaddition reaction. As described in Figure 1, the desired hybrids were designed by the incorporation of these two heterocycles through a thiosemicarbazone intermediate to combine the benefits of their electronic and structural effects.…”

“…According to these findings and to continue our efforts to discover other derivatives of monoterpenes and nucleoside analogs, which could also have interesting biological properties, [ 37–40 ] we report here the synthesis of new heterocyclic system hybrids incorporating isoxazoline and 1,3,4‐thiadiazole, using 1,3‐dipolar cycloaddition reaction. As described in Figure 1, the desired hybrids were designed by the incorporation of these two heterocycles through a thiosemicarbazone intermediate to combine the benefits of their electronic and structural effects.…”

Synthesis, Anticancer and Antibacterial Activity of Mannose-based bis-1,2,3-Triazole Derivatives

“…Mimicking glycosides, Nerella and co-workers 7 built new1,2,3-triazoles based on carbohydrate molecule that have notable anticancer activity against breast and prostate cancer cell lines. Recently, Oubella et al 8 synthesized series of novel (R)-Carvone-based 1,4-disubistituted-1,2,3-triazoles via regioselective cupper (I)-catalyzed alkyne-azide click methodology. The hybrids Carvone triazoles in vitro evaluated the anticancer activity against breast adenocarcinoma (MCF-7 and MDA-MB-231), (HT-1080) and fibro sarcoma (A-549) lung carcinoma, cell line.…”