Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Abstract

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

1,2,3‐Triazole hybrids as anticancer agents: A review

“…[89] 4-(Pyridin-4yloxy)benzamide derivatives containing a 1,2,3-triazole (96) showed stronger inhibitory activity than golvatinib, with IC 50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. [90] 1,2,3-Triazole-tethered moxifloxacin-isatin hybrid 97 showed promising cytotoxicity, with an IC 50 value of 44.2 μM against A549 cells, which was better than vorinostat (IC 50 value of 76.3 μM). [91] 1,2,3-Triazole containing quinazolin-4(3H)-one derivative 98 demonstrated significant activity, with an IC 50 value of 2.01 μM, compared to doxorubicin (IC 50 value of 1.29 μM) and was six times more potent than 5FU (IC 50 value of 13.45 μM).…”

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

“…An antiproliferative SAR study of 1,2,3-triazole-containing pyridine derivatives 38 against A549 cells demonstrates that the methyl group on the 1,2,3-triazole motif and the fluoro on the phenyl ring are advantageous to the activity (Xiong et al, 2020). The morpholino group is essential for high activity, while replacement by pyrrolidinyl, thienyl, and alkyl groups leads to great loss of activity.…”

Predictions of Drug–Protein Interactions and Study of Magnetically Assisted Release Dynamics of 5-Fluorouracil from Soya Protein-Coated Iron Oxide Core–Shell Nanoparticles

“…Although the efficacy of cyclophosphamide is exceptionally good in cancer treatment, destruction of healthy tissues at the same time is well known and reported. This issue of nonspecific toxicity caused by anticancer drugs − has been successfully tackled by encapsulating 5-fluorouracil drugs within a matrix of magnetic nanocarriers that deliver them effectively to the diseased site, sparing the healthy cells . , …”