ABSTRACT
KF-mediated nucleophilic activation of TMSCN as a functional isonitrile equivalent establishes an efficient and chemoselective Ugi-type multicomponent reaction of a heterocyclic amidine and aldehyde with TMSCN in water. In this approach, the use of isocyanide is circumvented, known competing reactions are virtually eliminated, pure products are obtained by a non-chromatographic method, and therapeutically relevant and diverse N-fused 3-aminoimidazoles can be prepared from a wide variety of aldehydes and heterocyclic amidines. This reaction coupling with cascade cyclization provides various privileged tetracyclic heteroaromatic scaffolds.
Subject(s)
Aldehydes/chemistry , Benzamidines/chemistry , Cyanides/chemistry , Fluorides/chemistry , Imidazoles/chemical synthesis , Potassium Compounds/chemistry , Trimethylsilyl Compounds/chemistry , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , Nitriles , Stereoisomerism , WaterABSTRACT
1-Methylimidazole exhibits an unusually high efficiency in promoting the reaction of aryl methyl ketones with DMF-DMA to form (2E)-1-aryl-3-dimethylamino-2-propenones which lacks correlation between the catalytic efficiency and the basicity of 1-methylimidazole in comparison to other amines. An unprecedented supramolecular domino catalysis rationalises the lack of correlation between the catalytic efficiency and basicity of the amines. The supramolecular assemblies have been characterized by mass-spectrometric ion fishing. The time-dependent increase/decrease in the concentration (ion current) of the supramolecular species consolidated the mechanism.
Subject(s)
Amines/chemistry , Dimethylformamide/analogs & derivatives , Ketones/chemistry , Propane/chemical synthesis , Catalysis , Dimethylformamide/chemistry , Macromolecular Substances/chemistry , Molecular Structure , Propane/analogs & derivatives , Propane/chemistryABSTRACT
On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , DNA-Binding Proteins/antagonists & inhibitors , G1 Phase , Heterocyclic Compounds, 2-Ring/chemical synthesis , Imidazoles/chemical synthesis , Models, Molecular , S Phase , Topoisomerase II Inhibitors/chemical synthesis , Adenosine Triphosphatases/chemistry , Adenosine Triphosphate/chemistry , Animals , Antigens, Neoplasm , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , DNA Topoisomerases, Type II , Drug Screening Assays, Antitumor , Etoposide/pharmacology , Fluorouracil/pharmacology , HEK293 Cells , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Molecular Dynamics Simulation , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Vero CellsABSTRACT
With the development of a novel microwave-assisted one-pot tandem de-tert-butylation of tert-butyl amine in an Ugi-type multicomponent reaction product, tert-butyl isocyanide as a useful convertible isonitrile has been explored for the first time affording access to molecular diversity of pharmaceutically-important polycyclic N-fused imidazo-heterocycles.
