Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors

Abstract

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.

Synthesis, cytotoxic evaluation, and molecular docking studies of some new 1, 3, 4-oxadiazole-based compounds

“…The binding location of reference ligand was defined as a binding site for finding the best pose of all ligands ( 24 25 26 ).…”

“…The molecular docking technique was conducted using the Autodock 4.2 software package, with the implemented empirical free energy function and the Lamarckian genetic algorithm ( 24 25 26 ).…”

Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds

“…In order to evaluate the cytotoxic effect of synthesized compounds, MTT reduction assay was performed as described previously (3334). Stock solutions of synthesized derivatives were prepared by their dissolving in DMSO.…”

Silicon switch: Carbon–silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug‐like properties in anticancer pharmacophores

“…In other studies, a series of hydrolytically stable silicon containing octahedral polypyridyl complexes ( 75–78 ) as illustrated in Figure 18, were reported for their DNA intercalating properties (Wheate et al, 2007; Xiang et al, 2012). Intercalators are a group of compounds that interact reversibly with the DNA double helix, some of which are currently in use for the treatment of ovarian and breast cancers, and acute leukemias, while others are in different phases of clinical trials (Khoshneviszadeh et al, 2021; Portugal & Barcelo, 2016; Sharma et al, 2021). The antitumor activity of intercalators is believed to be closely related to their ability to stabilize the DNA‐intercalator‐topoisomerase II ternary complex (Khoshneviszadeh et al, 2021; Portugal & Barcelo, 2016; Sharma et al, 2021).…”