Rational design and synthesis of novel quinazolinone N-acetohydrazides as type II multi-kinase inhibitors and potential anticancer agents

Abd El-Karim, Somaia S.; Syam, Yasmin M.; El Kerdawy, Ahmed M.; Abdel-Mohsen, Heba T.

doi:10.1016/j.bioorg.2023.106920

Cited by 9 publications

(4 citation statements)

References 41 publications

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“…Additionally, compound 16 revealed growth inhibition potential against NCI-60 cancer cell lines (GI50 = 1.64 µM). In addition, the same study showed that compound 16 led to cell cycle arrest in the MDA-MB-231 cell line at the G2/M phase alongside an apoptotic Abd El-Karim et al recently designed and discovered a novel class of quinazolinone N-acetohydrazides as significant inhibitors of VEGFR-2 alongside other kinases [44]. Compound 16 was the most potent candidate (Figure 7).…”

Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 94%

“…Abd El-Karim et al recently designed and discovered a novel class of quinazolinone N -acetohydrazides as significant inhibitors of VEGFR-2 alongside other kinases [ 44 ]. Compound 16 was the most potent candidate ( Figure 7 ).…”

Section: Quinazolines As Protein Kinases Inhibitorsmentioning

confidence: 99%

“…Moreover, agerafenib ( 15) is a potential anti-tumor agent and potent mutlikinase (VEGFR-2, PDGFR, BRAFWT, and BRAFV600E) inhibitor [43] (Figure 6). Abd El-Karim et al recently designed and discovered a novel class of quinazolinone N-acetohydrazides as significant inhibitors of VEGFR-2 alongside other kinases [44]. Compound 16 was the most potent candidate (Figure 7).…”

Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 99%

“…Thi mechanism represents the settlement of the quinazolinone scaffold within the hinge re gion of the target kinases, where the C=O forms a hydrogen bond with the importan amino acids. Meanwhile, the essential amino acids in the gate area interact through hy drogen bonding with the N-acetohydrazide linker and the peripheral phenyl moiety oc cupies the allosteric hydrophobic back pocket, producing a number of hydrophobic in teractions (Figure 7) [44]. Hamdi and colleagues [45] have successfully synthesized a novel series o 4-anilino-2-vinylquinazolines.…”

Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 99%

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Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Abdel-Mohsen,

Anwar,

Ahmed

et al. 2024

Molecules

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Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021–2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.

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Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 94%

Section: Quinazolines As Protein Kinases Inhibitorsmentioning

confidence: 99%

Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 99%

Section: Vascular Endothelia Growth Factor Receptor (Vegfr) Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Abdel-Mohsen,

Anwar,

Ahmed

et al. 2024

Molecules

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Quinazoline‐oxindole hybrids as angiokinase inhibitors and anticancer agents: Design, synthesis, biological evaluation, and molecular docking studies

Syam,

Abd El‐Karim,

Abdel‐Mohsen

2024

Archiv der Pharmazie

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Two new sets of quinazoline‐oxindole 8a–l and quinazoline‐dioxoisoindoline 10a–d hybrids were designed as type II angiokinase inhibitors and anticancer agents. The design strategy was adjusted to account for the quinazoline scaffold's placement in the target kinases' hinge region, where it would form hydrogen bonding and hydrophobic interactions with the important amino acids to stabilize it, and the amide group's occupation in the gate region, which would direct the oxindole scaffold toward the hydrophobic back pocket. The two sets of quinazolines 8a–l and 10a–d displayed pronounced inhibitory activity on VEGFR‐2 (IC50 = 0.46–2.20 µM). The quinazoline‐oxindole hybrids 8d, 8f, and 8h displayed IC50 = 0.46, 0.49, and 0.49 µM, respectively. Compound 8f demonstrated potent multikinase activity with IC50 values of 0.95 and 0.67 µM against FGFR‐1 and BRAF, respectively. Additionally, compound 8f showed significant anticancer activity against National Cancer Institute's cancer cell lines, with GI50 reaching 1.21 µM. Analysis of the impact of compound 8f on the MDA‐MB‐231 cell line's cell cycle and apoptosis revealed that 8f stalled the cell cycle at the G2/M phase and promoted its necrosis.

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Benzimidazole‐oxindole hybrids: A novel class of selective dual CDK2 and GSK‐3β inhibitors of potent anticancer activity

Abdel‐Mohsen,

Syam,

Abd El‐Ghany

et al. 2024

Archiv der Pharmazie

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A new series of benzimidazole‐oxindole hybrids 8a–x was discovered as dual cyclin‐dependent kinase (CDK2) and glycogen synthase kinase‐3‐beta (GSK‐3β) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single‐dose and five‐dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC‐1 cells with IC50 = 1.88–2.79 µM. In addition, the hybrids 8l, 8n, 8o, and 8p displayed potent antiproliferative activity on the MG‐63 cell line (IC50 = 0.99–1.90 µM). Concurrently, the benzimidazole‐oxindole hybrid 8v exhibited potent dual CDK2/GSK‐3β inhibitory activity with IC50 values of 0.04 and 0.021 µM, respectively. In addition, 8v displayed more than 10‐fold higher selectivity toward CDK2 and GSK‐3 β over CDK1, CDK5, GSK‐3α, vascular endothelial growth factor receptor‐2, and B‐rapidly accelerated fibrosarcoma. Screening of the effect of 8n and 8v on the cell cycle and apoptosis of PANC‐1 and MG‐63 cells displayed their ability to arrest their cell cycle at the G2‐M phase and to potentiate the apoptosis of both cell lines. In silico docking of the benzimidazole‐oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK‐3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a–x exhibit satisfactory drug‐likeness properties for drug development.

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Rational design and synthesis of novel quinazolinone N-acetohydrazides as type II multi-kinase inhibitors and potential anticancer agents

Cited by 9 publications

References 41 publications

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021–Present)

Quinazoline‐oxindole hybrids as angiokinase inhibitors and anticancer agents: Design, synthesis, biological evaluation, and molecular docking studies

Benzimidazole‐oxindole hybrids: A novel class of selective dual CDK2 and GSK‐3β inhibitors of potent anticancer activity

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