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

Archiv der Pharmazie, Год журнала: 2024, Номер 357(10)

Опубликована: Июль 23, 2024

Abstract 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 activity against national cancer institute cell lines in single‐dose five‐dose assays. Moreover, the derivatives 8k , 8l 8n, 8o 8p demonstrated cytotoxic PANC‐1 cells IC 50 = 1.88–2.79 µM. In addition, 8n antiproliferative on MG‐63 line (IC 0.99–1.90 µM). Concurrently, hybrid 8v exhibited CDK2/GSK‐3β inhibitory values 0.04 0.021 µM, respectively. more than 10‐fold higher selectivity toward CDK2 GSK‐3 β over CDK1, CDK5, GSK‐3α, vascular endothelial growth factor receptor‐2, B‐rapidly accelerated fibrosarcoma. Screening effect cycle apoptosis their ability to arrest at G2‐M phase potentiate both lines. silico docking into catalytic pocket GSK‐3β revealed its perfect fitting through formation hydrogen bonding hydrophobic interactions key amino acids binding sites. absorption, distribution, metabolism, excretion studies proved that exhibit satisfactory drug‐likeness properties for drug development.

Язык: Английский

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

Archiv der Pharmazie, Год журнала: 2024, Номер 357(10)

Опубликована: Июль 12, 2024

Two new sets of quinazoline-oxindole 8a-l and quinazoline-dioxoisoindoline 10a-d hybrids were designed as type II angiokinase inhibitors anticancer agents. The design strategy was adjusted to account for the quinazoline scaffold's placement in target kinases' hinge region, where it would form hydrogen bonding hydrophobic interactions with important amino acids stabilize it, amide group's occupation gate which direct oxindole scaffold toward back pocket. two quinazolines displayed pronounced inhibitory activity on VEGFR-2 (IC

Язык: Английский

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Discovery of novel diaryl urea-oxindole hybrids as BRAF kinase inhibitors targeting BRAF and KRAS mutant cancers

Bioorganic Chemistry, Год журнала: 2024, Номер 153, С. 107848 - 107848

Опубликована: Сен. 27, 2024

Язык: Английский

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Spiroindoline quinazolinedione derivatives as inhibitors of P-glycoprotein: potential agents for overcoming multidrug resistance in cancer therapy

Molecular Diversity, Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

Язык: Английский

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Green synthesis, in silico modeling, and biological evaluation of N-substituted (Z)-5-arylidene imidazolidine/thiazolidine-2,4-dione/4-thione derivatives catalyzed by Bu SO₃H core–shell nanostructures

RSC Advances, Год журнала: 2024, Номер 14(32), С. 22916 - 22938

Опубликована: Янв. 1, 2024

The newly designed magnetic nanocatalyst Fe 3 O 4 @CPTMS@guanidine–BuSO H in a one-pot multicomponent reaction is reported to obtain N -substituted ( Z )-5-arylidene imidazolidine/thiazolidine-2,4-dione/4-thione as highly selective antiproliferation agent.

Язык: Английский

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Diphenyl urea‐benzylidene acetohydrazide hybrids as fibroblast growth factor receptor 1 inhibitors and anticancer agents

Drug Development Research, Год журнала: 2024, Номер 85(6)

Опубликована: Авг. 24, 2024

Abstract Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series FGFR‐1 targeting cancer. The designed synthesized submitted to NCI‐USA be screened their growth inhibitory activity on NCI cancer cell lines. Some hybrids displayed promising lines with mean GI% 70.39% lethal effect. Compounds 9a , 9i 9j 9n‐p were further selected five‐dose assay all tested candidates showed antiproliferative GI 50 reaching submicromolar range. Encouraged by potent colon one hand well‐known overexpression in it other hand, as representative example evaluated its mechanism cycle apoptosis HCT116 line. Interestingly, found pause line at G1 phase induced late apoptosis. In parallel, 9a‐p examined potential inhibit 10 µM. 9g 9h 9p have % inhibition = 63.04%, 58.31%, 60.87% 79.84%, respectively. docking simulation binding pocket confirms capability achieve characteristic interactions type II inhibitors. Exploration ADME properties SwissADME web tool proved satisfactory physicochemical discovery anticancer hits.

Язык: Английский

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Benzimidazole–dioxoisoindoline conjugates as dual VEGFR-2 and FGFR-1 inhibitors: design, synthesis, biological investigation, molecular docking studies and ADME predictions

RSC Advances, Год журнала: 2024, Номер 14(39), С. 28889 - 28903

Опубликована: Янв. 1, 2024

A series of new benzimidazole–dioxo(benzo)isoindoline conjugates were designed and synthesized as dual VEGFR-2 FGFR-1 inhibitors. Compound 8m demonstrated potent % inhibition 80.69% 76.83% on at 10 μM, respectively.

Язык: Английский

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Oxindole–benzothiazole hybrids as CDK2 inhibitors and anticancer agents: design, synthesis and biological evaluation

BMC Chemistry, Год журнала: 2024, Номер 18(1)

Опубликована: Сен. 13, 2024

Abstract In the current study, molecular hybridization between oxindole core and benzothiazole system through an acetohydrazide moiety was accomplished for design of a new series oxindole–benzothiazole hybrids 9a – r targeting CDK2 cancer therapy. The afforded displayed promising growth inhibitory activity on NCI cell lines at 10 µM. Compound 9o mean GI% = 55.91%. Based potent , it further assessed its cytotoxic five dose level demonstrated GI 50 reaching 2.02 Analysis cycle prostate line DU145 after treatment with confirmed ability to arrest G1 phase. Moreover, proved potentiate apoptosis necrosis same line. Furthermore, 9b 9f showed IC 0.70, 0.20 0.21 µM, respectively CDK2. Besides, docking simulation synthesized hybrid expected binding mode which involves accommodation in ATP pocket where is involved hydrogen bonding hydrophobic interactions essential amino acids hinge region while oriented toward solvent region. Investigation physicochemical properties highlights their acceptable ADME that can be somewhat developed discovery anticancer agents.

Язык: Английский

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Pd-catalysed regioselective cross dehydrogenative coupling of quinazolinones with aromatic carboxylic acids

Tetrahedron Letters, Год журнала: 2024, Номер 147, С. 155214 - 155214

Опубликована: Июль 23, 2024

Язык: Английский

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Design, synthesis, and antiproliferative activity of new 1,2,3-triazole/quinazoline-4-one hybrids as dual EGFR/BRAF^V600E inhibitors

RSC Advances, Год журнала: 2024, Номер 14(52), С. 38403 - 38415

Опубликована: Янв. 1, 2024

A series of new quinazoline/1,2,3-triazole hybrids were designed and synthesized. The compounds evaluated as antiproliferative agents targeting EGFR, BRAF V600E .

Язык: Английский

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