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

Bahaa G.M. Youssif, Mostafa H. Abdelrahman, Ahmed H. Abdelazeem, Mohamed A. abdelgawad, Hussein M. Ibrahim, Ola I.A. Salem, Mamdouh F.A. Mohamed, Laurent Treambleau, Bukhari Syed Nasir Abbas

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)260-273
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume146
DOIs
Publication statusPublished - 25 Feb 2018
Externally publishedYes

Fingerprint

Antineoplastic Agents
Inhibitory Concentration 50
Reactive Oxygen Species
Antioxidants
Molecules
Assays
Proto-Oncogene Proteins B-raf
Chlorpyrifos
Reaction intermediates
Tubulin
Phagocytosis
Scaffolds
Aspirin
Testis
Cells
Cell Line
indole
Neoplasms
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

Keywords

  • Anti-cancer
  • Anti-oxidant
  • BRAF
  • Docking
  • EGFR
  • Indole-2-carboxamides
  • Pyrazino[1,2-a]indole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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. / 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; Syed Nasir Abbas, Bukhari.

In: European Journal of Medicinal Chemistry, Vol. 146, 25.02.2018, p. 260-273.

Research output: Contribution to journalArticle

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 ; Syed Nasir Abbas, Bukhari. / 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. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 146. pp. 260-273.
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abstract = "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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T1 - 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

AU - Youssif, Bahaa G.M.

AU - Abdelrahman, Mostafa H.

AU - Abdelazeem, Ahmed H.

AU - abdelgawad, Mohamed A.

AU - Ibrahim, Hussein M.

AU - Salem, Ola I.A.

AU - Mohamed, Mamdouh F.A.

AU - Treambleau, Laurent

AU - Syed Nasir Abbas, Bukhari

PY - 2018/2/25

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N2 - 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.

AB - 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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