ABSTRACT
A simple and efficient method for the one-pot synthesis of novel 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-1,5-dicarbaldehydes via the Vilsmeier-Haack reaction of the corresponding 7-acetyl-2-arylindoles has been developed. The mechanism of this reaction is envisaged to involve initial C-3 formylation and subsequent diformylation at the acetyl group with the excess Vilsmeier-Haack reagent followed by heteroannulation of the six-membered ring with concomitant extrusion of dimethylamine to afford the 1,2,5,8-tetrasubstituted pyrroloquinolinones. The highlight of this method is the construction of carbon-carbon and carbon-nitrogen bonds in a single-pot operation to afford polycarbo-substituted pyrroloquinolinones.
ABSTRACT
A series of indole-aminoquinazolines was prepared via amination of the 2-aryl-4-chloroquinazolines with the 7-amino-2-aryl-5-bromoindoles. It was then evaluated for cytotoxicity in vitro against human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A), breast adenocarcinoma (MCF-7), and cervical cancer (HeLa) cells. A combination on the quinazoline and indole moieties of a 2-phenyl and 2-(4-fluorophenyl) rings in compound 4b; 2-(4-fluorophenyl) and 3-chlorophenyl rings in compound 4f; or the two 2-(4-fluorophenyl) rings in compound 4g, resulted in significant and moderate activity against the Caco-2 and C3A cell lines. The indole-aminoquinazoline hybrids compounds 4f and 4g induced apoptosis in Caco-2 and C3A cells, and were also found to exhibit moderate (IC50 = 52.5 nM) and significant (IC50 = 40.7 nM) inhibitory activity towards epidermal growth factor receptor (EGFR) against gefitinib (IC50 = 38.9 nM). Molecular docking suggests that 4aâ»h could bind to the ATP region of EGFR like erlotinib.
Subject(s)
Aminoquinolines/chemistry , Antineoplastic Agents/pharmacology , Indoles/chemistry , Molecular Docking Simulation , A549 Cells , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Caco-2 Cells , Cell Line, Tumor , ErbB Receptors/metabolism , Gefitinib , HeLa Cells , Humans , MCF-7 Cells , Molecular Structure , Quinazolines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of novel N-((2,5-diaryl-3-trifluoroacetyl)-1H-indol-7-yl)acetamides has been prepared via a successive and one-pot reaction sequence involving initial trifluoroacetic acid-mediated Beckmann rearrangement of the oximes derived from the 1-(2,5-diaryl-1H-indol-7-yl)ethanones, followed by trifluoroacetylation of the incipient N-(2,5-diaryl-1H-indol-7-yl)-acetamides with trifluoroacetic anhydride. The prepared compounds were evaluated for potential in vitro antiplasmodial properties. Preliminary results from antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum revealed that a combination of 2-(4-flurophenyl)- and 5-(4-fluorophenyl) or 2-(4-flurophenyl)- and 4-fluorostyryl groups in compounds 3(a,f) and 4(a,g), for example, is required for biological activity for both series of compounds. Their possible mode of action against the plasmodial parasite is explained theoretically through molecular docking of the most active compounds against the parasite lactate dehydrogenase (pLDH). These compounds were docked at the entrance of NAD+ in pLDH presumably hindering entry of lactate to cause the observed inhibition effect of pLDH. The four compounds were found to exhibit low toxicity against monkey kidney Vero cells at the highest concentrations tested.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Acetamides/chemistry , Animals , Antimalarials/chemistry , Chlorocebus aethiops , Chloroquine/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Molecular Docking Simulation , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Protozoan Proteins/antagonists & inhibitors , Structure-Activity Relationship , Vero CellsABSTRACT
A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki-Miyaura cross-coupling of 2-amino-5-bromo-3-iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl-substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Acetophenones/chemical synthesis , Acetophenones/chemistry , Acetophenones/pharmacology , Amination , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Cell Proliferation/drug effects , Female , Halogenation , HeLa Cells , Humans , Indoles/chemical synthesis , MCF-7 Cells , Uterine Cervical Neoplasms/drug therapyABSTRACT
Iodine-catalyzed condensation of 2-amino-3,5-dibromobenzamide with cyclohexane-1,3-dione derivatives in refluxing toluene afforded the corresponding bisquinazolinones. Suzuki-Miyaura cross-coupling of the latter with arylboronic acids afforded tetraarylbisquinazolinones. The electronic absorption and emission properties of these tetraarylbisquinazolinones were measured in dimethylsulfoxide (DMSO) and acetic acid by means of UV-Vis and fluorescence spectroscopic techniques in conjunction with quantum chemical methods to understand the influence of substituents on intramolecular charge transfer (ICT).
