Design, Synthesis, and Biological Evaluation of 2-Mercaptobenzoxazole Derivatives as Potential Multi-Kinase Inhibitors

Alanazi, Mohammed M.; Aldawas, Saleh; Alsaif, Nawaf A.

doi:10.3390/ph16010097

Cited by 13 publications

(5 citation statements)

References 46 publications

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“…Specifically, the following ELISA kits were utilized: KHO1091 (InvitrogenTM, Grand Island, NY, USA) for caspase-3, EIA-4860 and EIA-4487 for BAX, (DRU International INC., Mountainside, NJ, USA), and 99-0042 (InvitrogenTM, Grand Island, NY, USA) for Bcl-2 for the respective measurements. The experimental procedures were conducted according to the instructions provided by the manufacturers and our recently published article [ 31 , 34 , 36 , 37 ]. Initially, HepG2 cells were cultured in triplicate in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Molecular docking analysis of compound 5k with the ATP active binding pockets of CDK2, EGFR, Her2, and VEGFR2 were studied according to the previously described methods [ 34 , 37 ]. The X-ray crystal structures of the EGFR kinase domain bound to erlotinib (PDB ID: 4HJO), the VEGFR2 kinase domain bound to sorafenib (PDB ID: 4ASD), the kinase domain of human Her2 bound to TAK-285 (PDB ID: 3RCD), and the CDK2 kinase bound to sunitinib were acquired from The Protein Data Bank ( , (accessed on 5 June 2023).…”

Section: Methodsmentioning

confidence: 99%

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Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

Alotaibi,

Alanazi,

Rahman

2023

Pharmaceuticals

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In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(E)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely 5e, 5h, 5k, and 5l, promising cytotoxic effects were observed against four different cancer cell lines, with IC50 values ranging from 29 to 59 µM. Notably, compound 5k emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC50 values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC50 = 261 nM). Mechanistic investigations of compound 5k revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound 5k and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound 5k as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

Alotaibi,

Alanazi,

Rahman

2023

Pharmaceuticals

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“…The apoptotic and necrotic effect of compound 5d was investigated using flow cytometry, as described in [ 43 ]. The HepG2 cells were treated with 7.1 µM of compound 5d for 24 h. After treatment, the cells were collected by trypsinization, centrifuged, and washed two times with PBS.…”

Section: Methodsmentioning

confidence: 99%

Novel 2-Sulfanylquinazolin-4(3H)-one Derivatives as Multi-Kinase Inhibitors and Apoptosis Inducers: A Synthesis, Biological Evaluation, and Molecular Docking Study

et al. 2023

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The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, 5d, showed broad-spectrum anti-cancer activities against all tested cell lines (IC50 = 1.94–7.1 µM) in comparison to doxorubicin (IC50 = 3.18–5.57 µM). Interestingly, compound 5d exhibited lower toxicity in the normal WI-38 cells (IC50 = 40.85 µM) than doxorubicin (IC50 = 6.72 µM), indicating a good safety profile. Additionally, the potential of compound 5d as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound 5d exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound 5d was the least active against CDK2 (2.097 ± 0.126 µM) when compared to the positive control roscovitine (0.32 ± 0.019 µM). The apoptotic activity investigation in HepG2 cells demonstrated that compound 5d arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound 5d showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors.

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“…Molecular docking studies of synthesized compounds docked into the active sites of selected protein kinases were performed using AutoDock Vina and PyRx (The Scripps Research Institute, La Jolla, CA, USA) software (0.8) and visualized by Discovery studio visualizer, as described in [17,19,31].…”

Section: Molecular Dockingmentioning

confidence: 99%

Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation

Alanazi

2023

Molecules

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Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-targeted therapy, such as targeting the abnormal cell signaling inside the cancer cells. Targeted chemotherapy is effective in several malignancies; however, the success has always been limited by drug resistance and/or side effects. Anticancer with multi-targeted actions simultaneously modulates multiple cancer cell signaling pathways and, therefore, may ease the chance of effective anticancer drug development. In this research, a series of 7-deazapurine incorporating isatin hybrid compounds was designed and successfully synthesized. Among those hybrids, compound 5 demonstrated a very potent cytotoxic effect compared to the reference anticancer drug against four cancer cell lines. Likewise, compound 5 inhibited the activity of four protein kinase enzymes in nanomolar ranges. Further analysis of the biological evaluation of compound 5 revealed the capability of compound 5 to arrest cell cycle progression and induce programmed cell death. Moreover, molecular simulation studies were performed to investigate the possible types of interactions between compound 5 and the investigated protein kinases. Finally, taking into consideration all the abovementioned findings, compound 5 could be a good candidate for further investigations.

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Design, Synthesis, and Biological Evaluation of 2-Mercaptobenzoxazole Derivatives as Potential Multi-Kinase Inhibitors

Cited by 13 publications

References 46 publications

Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers

Novel 2-Sulfanylquinazolin-4(3H)-one Derivatives as Multi-Kinase Inhibitors and Apoptosis Inducers: A Synthesis, Biological Evaluation, and Molecular Docking Study

Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation

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