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

• 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: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.02.2018; Elsevier
• 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; Chemistry, Medicinal; Docking; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; EGFR; Humans; Indole-2-carboxamides; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Male; Mice; Models, Molecular; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Pharmacology & Pharmacy; 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; Science & Technology; 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; OXIDATIVE STRESS; LIPID-PEROXIDATION; ANTIOXIDANTS; CHEMILUMINESCENCE; CANCER; DISCOVERY; FREE-RADICALS; CHLORPYRIFOS; INHIBITORS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.01.042

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.