Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

Barakat, Assem; Alshahrani, Saeed; Al‐Majid, Abdullah Mohammed; Alamary, Abdullah Saleh; Haukka, Matti; Abu‐Serie, Marwa M.; Dömling, Alexander; Mazyed, Eman A.; Badria, Farid A.; El-Senduny, Fardous F.

doi:10.1016/j.bioorg.2022.106124

Cited by 8 publications

(8 citation statements)

References 70 publications

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“…The anticancer activity protocol was carried out according to the method reported in [48]. "The cytotoxicity of tested compounds was investigated on a human normal lung fibroblast (Wi-38) cell line, triple-negative breast (MDA-MB 231) cells, and prostate cancer (PC3) cells.…”

Section: Anticancer Activity Protocolmentioning

confidence: 99%

“…The absorbance was measured at 590 nm (BMG LabTech, Ortenberg, Germany). The half-inhibitory growth concentration (IC 50 ) was calculated by GraphPad Prism software" [48].…”

Section: Anticancer Activity Protocolmentioning

confidence: 99%

“…Different electronic effects on the aromatic ring, including electron-donating and electron-withdrawing effects, also achieved a heterocycle aromatic ring and were explored. The synthetic methodology was carried out based on a multicomponent one-pot reaction via the [3+2] cycloaddition reaction approach [48]. The desired dipolarphiles were synthesized from orthophenylene diamine in a consequential step.…”

Section: Chemistrymentioning

confidence: 99%

“…Our research group has engaged in this research program for a couple of years and has been successful in designing and developing several molecules towards PPI [35][36][37][38][39]. Among the discovered molecules, a new spiroxindole [48], as a rigid structure with a combination of benzimidazole scaffold, has been discovered as a novel MDM2 protein inhibitor with dual effects of antimetastatic efficacy. Based on these findings, we have rationally designed and synthesized a new spirooxindoles-based benzimidazole unit as an MDM2 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Rational Design, Synthesis, Separation, and Characterization of New Spiroxindoles Combined with Benzimidazole Scaffold as an MDM2 Inhibitor

et al. 2023

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Rational design for a new spiroxindoles, combined with a benzimidazole scaffold to identify a new murine double minute two (MDM2) inhibitor was synthesized and characterized. The desired spiroxindoles were achieved via a [3+2] cycloaddition reaction approach which afforded the cycloadducts with four asymmetric centers separated in an excellent regioselective and diastereoselective compound. The separated spiroxindoles were subjected to a set of biochemical assays including an NCI cell panel assay, MTT assay, and MDM2 binding analysis by a microscale thermophoresis assay. The anticancer reactivity for the tested compounds showed IC50 (µM) in the range between 3.797–6.879 µM, and compound 7d with IC50 = 3.797 ± 0.205 µM was the most active candidate between the series. The results showed promising results that identified that compound 7a could be inhibited the MDM2 with KD = 2.38 μm. Compound 7a developed a network of interactions with the MDM2 receptor studied in silico by molecular docking.

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Section: Anticancer Activity Protocolmentioning

confidence: 99%

“…The absorbance was measured at 590 nm (BMG LabTech, Ortenberg, Germany). The half-inhibitory growth concentration (IC 50 ) was calculated by GraphPad Prism software" [48].…”

Section: Anticancer Activity Protocolmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rational Design, Synthesis, Separation, and Characterization of New Spiroxindoles Combined with Benzimidazole Scaffold as an MDM2 Inhibitor

et al. 2023

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“…In continuation of our previous work (Barakat et al, 2022;Barakat et al, 2023) we followed diversityoriented synthesis (DOS) guided by the above information, we have designed spirooxindole-pyrrolidine skeleton framework containing pyrazole and thiochromene to discover new candidates thereby, possessing αamylase inhibitors.…”

mentioning

confidence: 99%

A novel alpha‐amylase inhibitor‐based spirooxindole‐pyrrolidine‐clubbed thiochromene‐pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory

Islam,

Al‐Majid,

Haukka

et al. 2023

Chem Biol Drug Des

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A novel spirooxindole‐pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene‐based thiochromene and pyrazole scaffolds with the secondary amino‐acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS‐on is 13.9 kcal mol−1 below the separated reagent. This 32CA, which takes place through a non‐concerted one‐step mechanism, presents a total ortho regio‐ and endo stereoselectivity, which is controlled by the formation of two intramolecular H…O hydrogen bonds. The design of spirooxindole‐pyrrolidines engrafted thiochromene and pyrazole was tested for alpha‐amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole‐pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

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p53 as a potential target for treatment of cancer: A perspective on recent advancements in small molecules with structural insights and SAR studies

Chahat¹,

Bhatia²,

Kumar

2023

European Journal of Medicinal Chemistry

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Novel spirooxindole based benzimidazole scaffold: In vitro, nanoformulation and in vivo studies on anticancer and antimetastatic activity of breast adenocarcinoma

Cited by 8 publications

References 70 publications

Rational Design, Synthesis, Separation, and Characterization of New Spiroxindoles Combined with Benzimidazole Scaffold as an MDM2 Inhibitor

Rational Design, Synthesis, Separation, and Characterization of New Spiroxindoles Combined with Benzimidazole Scaffold as an MDM2 Inhibitor

A novel alpha‐amylase inhibitor‐based spirooxindole‐pyrrolidine‐clubbed thiochromene‐pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory

p53 as a potential target for treatment of cancer: A perspective on recent advancements in small molecules with structural insights and SAR studies

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