Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors

Elagawany, Mohamed; Ibrahim, Mohamed A.; Ahmed, Hany E. A.; El‐Etrawy, A. Sh.; Ghiaty, Adel; Abdel‐Samii, Zakaria K.; El‐Feky, Said A.; Bajorath, Jürgen

doi:10.1016/j.bmcl.2013.02.027

Cited by 29 publications

(16 citation statements)

References 24 publications

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“…On the other hand, with dual specificity, DYRK1A plays a key role in Down syndrome and Alzheimer's disease. In addition, DYRK1A has been shown to be expressed ubiquitously, and its functional role in cancer is still largely obscure, however several compounds caused inhibition of this kinase in HL-60 cells, decreasing its proliferation in vitro [37]. In order to elucidate how the 3c molecule interacts with CDK2, a detailed docking study was conducted, also including compound 3g for comparison reasons.…”

Section: Molecular Modelingmentioning

confidence: 99%

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

et al. 2019

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Fourteen arylsemicarbazone derivatives were synthesized and evaluated in order to find agents with potential anticancer activity. Cytotoxic screening was performed against K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29 and MCF-7 tumor cell lines. Compounds 3c and 4a were active against the tested cancer cell lines, being more cytotoxic for the HL-60 cell line with IC50 values of 13.08 μM and 11.38 μM, respectively. Regarding the protein kinase inhibition assay, 3c inhibited seven different kinases and 4a strongly inhibited the CK1δ/ε kinase. The studied kinases are involved in several cellular functions such as proliferation, migration, cell death and cell cycle progression. Additional analysis by flow cytometry revealed that 3c and 4a caused depolarization of the mitochondrial membrane, suggesting apoptosis mediated by the intrinsic pathway. Compound 3c induced arrest in G1 phase of the cell cycle on HL-60 cells, and in the annexin V assay approximately 50% of cells were in apoptosis at the highest concentration tested (26 μM). Compound 4a inhibited cell cycle by accumulation of abnormal postmitotic cells at G1 phase and induced DNA fragmentation at the highest concentration (22 μM).

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Section: Molecular Modelingmentioning

confidence: 99%

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

et al. 2019

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“…Zopolrestat Luminal Hydrazine Fig. 1: Some commercially used phthalazine drugs www.bosaljournals/chemint/ editorci@bosaljournals.com findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors (Elagawany et al, 2013). Poly(phthalazinone-ether-sulfone) (PPES) polymer is a relatively newly developed material with a bis(4-fluorodiphenyl) sulfone group.…”

Section: Azelastinmentioning

confidence: 99%

Pharmacological activities of various phthalazine and phthalazinone derivatives

Int¹

2019

Preprint

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Various pthalazine derivatives have been synthesized and tested for their diverse biological activities. Pthalazine derivatives have been exhibited pharmacological activities like antitumor, PARP-1 inhibitors, antimicrobial, antivirus, antihistamine-H1, antiallergic rhinitis, antifungal, anti-inflammatory, anti-proliferative, COX-2 inhibitor, LOX-5 inhibitor, antidiabetes, and other biological activities like imaging agent. Pthalazine derivatives were also used as agrochemicals and chemicals. Various synthetic aspects indicate that pthalazines derivatives are easy to synthesize which can produce a wide variety of activity.

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“…We looked to modify the methylpyrazin-2(1H)-one with alternate heterocycles that could offer another H-bonding opportunity with the protein. Amino-pyridazinones have been reported to be efficient kinase hinge binders 9 that have the potential to form three H-bonds with the hinge region. Additionally, from ongoing work in a related chemical series, 10 we had discovered that a 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine in the solvent exposed region improved biochemical potency over the dimethyl-2-piperazinone group within 1, and that oxidation of the tetrahydrobenzo[b]thiophene to a benzothiophene ring offered improved metabolic stability, in most analogs, as well.…”

Section: Figurementioning

confidence: 99%

Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability

Young¹,

Barbosa

Blomgren

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.

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Design, synthesis, and molecular modelling of pyridazinone and phthalazinone derivatives as protein kinases inhibitors

Cited by 29 publications

References 24 publications

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents

Pharmacological activities of various phthalazine and phthalazinone derivatives

Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability

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