Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production

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 again...

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Published in:	European journal of medicinal chemistry Vol. 146; pp. 260 - 273
Main Authors:	Youssif, Bahaa G.M., Abdelrahman, Mostafa H., Abdelazeem, Ahmed H., abdelgawad, Mohamed A., Ibrahim, Hussein M., Salem, Ola I.A., Mohamed, Mamdouh F.A., Treambleau, Laurent, Bukhari, Syed Nasir Abbas
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 25-02-2018
Subjects:	Animals Anti-cancer Anti-oxidant Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antioxidants - chemical synthesis Antioxidants - chemistry Antioxidants - pharmacology BRAF Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Docking Dose-Response Relationship, Drug Drug Design Drug Screening Assays, Antitumor EGFR Humans Indole-2-carboxamides Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Male Mice Models, Molecular Molecular Structure Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology Polymerization - drug effects Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - metabolism Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacology Pyrazino[1,2-a]indole Reactive Oxygen Species - metabolism Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - metabolism Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship Tubulin - metabolism Pyrazino[1,2-a]indole Indole-2-carboxamides Anti-oxidant Docking BRAF Anti-cancer EGFR
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Summary:	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. [Display omitted] •Two series of pyrazino[1,2-a]indol-1(2H)-one closed system and open indole derivatives have been synthesized.•The new compounds were evaluated for their anticancer and antioxidant activities.•The most active anticancer compounds were tested against EGFR, BRAF and Tubulin.•Histopathological and immunohistochemical studies of most potent derivatives were performed.•Docking study of the active compounds was done against EGFR and BRAF kinases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2018.01.042