Evaluation of Ethylated Phenylcarbamoylazinane‐1,2,4‐Triazole Amides Derivatives as 15‐Lipoxygenase Inhibitors Together with Cytotoxic, ADME and Molecular Modeling Studies
Abstract:Searching the organic compound as anti-inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N-alkyl/ aralkyl/aryl derivatives (7 a-o) of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide by the continuou… Show more
“…Figure 2 depicts the principal synthesis method for the production of Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives (M1–15) which has been reported in our previous work 39 . Figure 2 Synthesis of phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives 39 . …”
Section: Resultsmentioning
confidence: 99%
“…A general procedure for the synthesis of phenylcarbamoylpiperidine-1,2,4-triazole derivatives has been reported in our previous work 39 . The goal of this research is to look at the in-silico inhibitory potential of novel amide analogues of phenylcarbamoylpiperidine-1,2,4-triazole with diverse substituents (M1–M15).…”
Section: Methodsmentioning
confidence: 99%
“…This work explored the anticancer potential of novel N -alkyl/aralky/aryl derivatives (M1–M15) of 2-(4-phenyl-5-(1-phenylcarbamoyl) piperidine-4H-1, 2,4-triazol-3-ylthio)acetamide which have been synthesized and reported with the goal of disrupting inflammatory pathways and treating inflammatory disorders such as asthma and rheumatoid arthritis 39 . These derivatives are a heterocyclic class of compounds that interact with the receptor's active site by accepting and donating electrons and creating hydrogen bonds with the activation loop's amino acid residues.…”
Section: Introductionmentioning
confidence: 99%
“…The purpose of this research was to identify a new physiologically active marcapto of 1,2,4-triazole amide that might provide as a strong lead for NEK7 inhibitor development. Figure 1 ( A ) Depiction of the most potent inhibitors of NEK7 which were previously identified as the potent inhibitors of lipoxygenase enzyme 39 . ( B ) Binding scores and binding affinity (ki) of potent derivatives against NEK7 ( C ) showing the Binding scores of Dabrafenib against NEK7: reported anti-cancer drug 38 .…”
Section: Introductionmentioning
confidence: 99%
“… ( A ) Depiction of the most potent inhibitors of NEK7 which were previously identified as the potent inhibitors of lipoxygenase enzyme 39 . ( B ) Binding scores and binding affinity (ki) of potent derivatives against NEK7 ( C ) showing the Binding scores of Dabrafenib against NEK7: reported anti-cancer drug 38 .…”
NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds' stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) software’s were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein–ligand complexes with docking scores of − 29.66 kJ/mol and − 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein–ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.
“…Figure 2 depicts the principal synthesis method for the production of Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives (M1–15) which has been reported in our previous work 39 . Figure 2 Synthesis of phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives 39 . …”
Section: Resultsmentioning
confidence: 99%
“…A general procedure for the synthesis of phenylcarbamoylpiperidine-1,2,4-triazole derivatives has been reported in our previous work 39 . The goal of this research is to look at the in-silico inhibitory potential of novel amide analogues of phenylcarbamoylpiperidine-1,2,4-triazole with diverse substituents (M1–M15).…”
Section: Methodsmentioning
confidence: 99%
“…This work explored the anticancer potential of novel N -alkyl/aralky/aryl derivatives (M1–M15) of 2-(4-phenyl-5-(1-phenylcarbamoyl) piperidine-4H-1, 2,4-triazol-3-ylthio)acetamide which have been synthesized and reported with the goal of disrupting inflammatory pathways and treating inflammatory disorders such as asthma and rheumatoid arthritis 39 . These derivatives are a heterocyclic class of compounds that interact with the receptor's active site by accepting and donating electrons and creating hydrogen bonds with the activation loop's amino acid residues.…”
Section: Introductionmentioning
confidence: 99%
“…The purpose of this research was to identify a new physiologically active marcapto of 1,2,4-triazole amide that might provide as a strong lead for NEK7 inhibitor development. Figure 1 ( A ) Depiction of the most potent inhibitors of NEK7 which were previously identified as the potent inhibitors of lipoxygenase enzyme 39 . ( B ) Binding scores and binding affinity (ki) of potent derivatives against NEK7 ( C ) showing the Binding scores of Dabrafenib against NEK7: reported anti-cancer drug 38 .…”
Section: Introductionmentioning
confidence: 99%
“… ( A ) Depiction of the most potent inhibitors of NEK7 which were previously identified as the potent inhibitors of lipoxygenase enzyme 39 . ( B ) Binding scores and binding affinity (ki) of potent derivatives against NEK7 ( C ) showing the Binding scores of Dabrafenib against NEK7: reported anti-cancer drug 38 .…”
NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds' stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) software’s were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein–ligand complexes with docking scores of − 29.66 kJ/mol and − 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein–ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.
Cancer is still one of the leading causes of death worldwide. Many researchers are working to design and develop heterocyclic-based drugs with the potential to treat cancer at various stages. There is always an unmet need to discover new anticancer drugs to treat different types of cancer. Based on literature reports, it was evident that hybrid 1,2,4-triazoles exhibit a wide spectrum of biological potential (particularly potent anticancer activity), as compared to the corresponding monocyclic compounds. In this review, we summarized fused/hybrid 1,2,4-triazole and poly-functionalized 1,2,4-triazoles as anticancer agents. Triazole may be fused with other heterocyclic scaffolds like pyrimidine, pyridine, piperidine, quinoxaline, quinazoline, thiadiazine, indole, phthalazine etc. A clear explanation of the method of synthesis, structure-activity relationship, and in vitro results plus the inhibitory concentration of new molecules are focused on in this review article.
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