ABSTRACT
A series of new indole derivatives 1-18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC50 value of 0.07 µM, which is more potent than that of sorafenib (0.09 µM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Indoles/pharmacology , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Bromination of visnaginone (1) yielded the dibromo derivative (2), which upon methylation with methyl iodide gave 1-(2,7-dibromo-4,6-dimethoxybenzofuran-5-yl) ethanone (3). Compound (3) reacted with dimethylformamide dimethylacetal to give (4). The reaction of (3) with aromatic aldehydes namely (vanillin, benzaldehyde and 3-anisaldehyde) in ammonium acetate, malononitrile and/or butyric cyanoanhydride gave the 2-amino substituted nicotinonitriles (5a-c) and the 2-hydroxyl substituted nicotinonitriles (7a-c), respectively, while in piperidine gave (E)-1-(2,7-dibromo-4,6-dimethoxybenzofuran-5-yl)-3-(substituted)prop-2-en-l-one (11a-c). (5a) was hydrolyzed with sulfuric acid on cold to give the nicotinic acid derivative (6a). When compound (3) reacted with hydrazines and aromatic amines, it gave the Schiff bases (8a,b) and (10a,b), respectively. (8b) reacted with thioglycolic acid to give the thiazolidin-4-one (9b). When (11a-c) reacted with thiourea, it gave the pyrimidine derivatives (12a-c). (11a,b) also reacted with butyric cyanoanhydride and hydroxylamine hydrochloride to give (13a,b) and (15a,b), respectively. When the carboxylate (13a) was treated with 2,4-dinitroaniline, it gave the carboxamide (14a). Compounds (11b,c) reacted with hydrazine derivatives (hydrazine hydrate and phenylhydrazine) yielding the substituted pyrazole derivatives (16b,c) and (17b,c), respectively. All the structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The newly synthesized benzofuran compounds showed a strong to moderate cytotoxicity against liver HEPG2 cancer cell line compared to 5-fluorouracil and doxorubicin (the anticancer agents). Compounds (2, 6a, 13a, 14a, 16c and 17b) were the most active compounds in descending order. The synthesized compounds were also tested for their antimicrobial activity. Compound (10b) showed the highest activity against all the tested strains followed by 6, 10a, 5a, 8b and 7a in descending order.
Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Benzofurans/pharmacology , Khellin/analogs & derivatives , Anti-Infective Agents/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Bacteria/drug effects , Bacteria/growth & development , Benzofurans/chemical synthesis , Cell Proliferation/drug effects , Cell Survival/drug effects , Disk Diffusion Antimicrobial Tests , Dose-Response Relationship, Drug , Doxorubicin/pharmacology , Fluorouracil/pharmacology , Fungi/drug effects , Fungi/growth & development , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Khellin/chemistry , Khellin/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
The starting material, 4-(1-indol-2-yl)phenol 1 was obtained via Fischer synthesis. Vilsmeir Haack(')s formylation of 1 gave the carboxaldehyde derivative 2 which was subjected to different reactions affording the 3-substituted compounds 3-10. Compound 1 reacted with halo esters to give 11 and 12a,b. The reaction of 12a with various amino derivatives gave compounds 13-16. The hydrazide derivative 15a reacted with 1,3-diketones, ethyl acetoacetate and aromatic carboxylic acid derivatives to give 17a,b, 18 and 19a-e, respectively. Antitumor activity of target compounds were tested against breast cancer cell lines (MCF-7) and (MDA-MB-231). The most potent compound was 3e with IC(50) = 1.60 nM against (MCF-7). Docking was performed on colchicine binding site of tubulin to study the binding mode of the designed compounds.
