Pyrazinoindolone inhibitors of MAPKAP-K2

doi:10.1016/j.bmcl.2007.12.037

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 3, 1 February 2008, Pages 938-941

https://doi.org/10.1016/j.bmcl.2007.12.037 Get rights and content

Abstract

Optimization of pyrazinoindolone inhibitors of MAPKAP-K2 (MK2) provides a reasonable balance of cellular potency and physicochemical properties. Mechanistic studies support the inhibition of MK2 which is responsible for the sub-micromolar cellular efficacy.

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Citation Excerpt :
He introduced many compounds containing either the carboline or pyrazinoindolone scaffold. Compound 82 was obtained as most potent inhibitor of DYRK1Aand their IC50 was found to be 94 nM [86]. From an exhaustive literature survey one study came out with the must have characters that a kinase inhibitor should possess: Planar hetero atomic rings with acceptor and donors [87].
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Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.
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A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a-g) and their reaction intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS generation during the metabolic phase of phagocytosis in a dose-dependent manner where compounds 5d and 5e were the most potent samples with higher inhibitory activities (IC₅₀ values 3.3 and 1.4 μM, respectively) than that of the reference acetylsalicylic acid (IC₅₀ = 9.7 μM). Results for the determination of potential antioxidant properties of the synthesized compounds showed that compounds 5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even comparable to Trolox. Compounds 3d-f and 5d-f with the least IC₅₀ values in MTT assay were tested against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical study were performed to determine the consequence of exposure to chronic low dose of chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by co-treatment with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies were performed to explore the binding mode of the most active compounds against EGFR and BRAF kinases.
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Pyrazinoindolone inhibitors of MAPKAP-K2

Abstract

Graphical abstract

Med. Res. Rev.

Ann. N.Y. Acad. Sci.

J. Chem. Soc., Trans.

Drug Des. Discov.

IUBMB Life

Nat. Cell Biol.

EMBO J.

Nat. Rev. Mol. Cell Biol.