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

Abstract

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.

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules

“…To increase the library of spirooxindole scaffolds as lead compounds for development of new drugs for cancer treatment targeting MDM2 inhibitors ( Alshahrani et al, 2023 ), new spirooxindole derivatives ( 6a–n ) were synthesized by the reaction of chalcones 3a–n ( Supplementary Table S1 ) with isatin 4 and thiazolidine-4-carboxylic acid 5 in methanol under reflux for 2–3 h, as shown in Scheme 1 . The new spiro-derivatives 6a–n was fully characterized by FT-IR, 1 H- and 13 C- NMR, and elemental analysis; spirooxindole analog 6i was characterized by single-crystal x-ray diffraction analysis (data provided in SI, Supplementary Tables S1–S4 ).…”

“…Elemental analysis was performed using an Elmer 2400 Elemental Analyzer in CHN mode. Chalcones 3a–n was prepared as reported previously by ( Alshahrani et al, 2023 )”.…”

New spiro-indeno[1,2- b ]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights

“…In Scheme 1 , the targeted new structurally complex and diverse benzimidazole-tethered indenoquinoxaline-based spiro-heterocycles 4a-h and 6a-h were synthesised. Considering the growing interest in multicomponent reactions gaining access to bioactive spiropyrrolidine derivatives 34 , 35 , we have synthesised the the title spiro compounds 4a-h and 6a-h via 32CA reaction of 11 H -indeno[1,2- b ]quinoxalin-11-one 2 with the benzimidazolyl chalcones 1a-h and L-proline or octahydroindole-2-carboxylic acid. The products of cycloaddition reaction were separated using silica gel (petroleum ether/ethyl acetate (4:1)) column chromatography.…”

Stereoselective Synthesis of a Novel Series of Dispiro-oxindolopyrrolizidines Embodying Thiazolo[3,2-a]benzimidazole Motif: A Molecular Electron Density Theory Study of the Mechanism of the [3 + 2] Cycloaddition Reaction

“…In a recent study they constructed a new spirooxindole compound including a thiazolo [3,2-a] benzimidazole pharmacophore and studied its chemical reactivity (Compound X, Figure 1) [15]. Due to the variety of spiro-compounds, in particular spriooxindoles, they have a wide range of biological targets including anti-cancer, anti-inflammatory, diabetes, and others [16][17][18][19][20].…”