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.