ABSTRACT
The rapid growth of serious infections caused by antibiotic resistant bacteria, especially the nosocomial ESKAPE pathogens, has been acknowledged by Governments and scientists and is one of the world's major health problems. Various strategies have been and are currently investigated and developed to reduce and/or delay the bacterial resistance. One of these strategies regards the design and development of antimicrobial hybrids and conjugates. This unprecedented critical review, in which our continuing interest in the synthesis and evaluation of the bioactivity of imidazole derivatives is testified, aims to summarise and comment on the results obtained from the end of the 1900s until February 2020 in studies conducted by numerous international research groups on the synthesis and evaluation of the antibacterial properties of imidazole-based molecular hybrids and conjugates in which the pharmacophoric constituents of these compounds are directly covalently linked or connected through a linker or spacer. In this review, significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics. However, it does not include literature data on the synthesis and evaluation of the bioactivity of hybrids and conjugates in which an imidazole moiety is fused with a carbo- or heterocyclic subunit.
Subject(s)
Anti-Bacterial Agents , Bacteria/growth & development , Bacterial Infections/drug therapy , Drug Resistance, Bacterial/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/microbiology , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/therapeutic use , Microbial Sensitivity TestsABSTRACT
Highly cytotoxic 1,5-diaryl-1H-imidazoles were studied to clarify the relationship between cytotoxicity and activity as vascular disrupting agents (VDA). All the compounds disorganized the tubulin cytoskeleton, affected endothelial cell morphology and capillary formation in vitro, and caused vessel shutdown and tumor necrosis in vivo, thus confirming their vascular disrupting properties. Nonetheless, the substitution patterns on the imidazole ring, responsible for greater interaction energy with tubulin and higher cytotoxicity, were not associated to greater vascular disrupting activity.
Subject(s)
Blood Vessels/drug effects , Imidazoles/pharmacology , Tubulin/metabolism , Animals , Binding Sites , Blood Vessels/metabolism , Cell Line, Tumor , Endothelial Cells/drug effects , Humans , Hydrochloric Acid/chemistry , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/toxicity , Isomerism , Mice , Neoplasms/blood supplyABSTRACT
A new method for the efficient, practical, and highly regioselective direct palladium-catalyzed C-3 arylation of free (NH)-indole and its electron-rich 1-unsubstituted derivatives under ligandless conditions is described. The reactions, which are run outside a glovebox without purification of solvent and reagents, involve treatment of free (NH)-indoles with activated, unactivated, and deactivated aryl bromides in refluxing toluene in the presence of K2CO3 as the base and a catalyst system consisting of a combination of Pd(OAc)2 and benzyl(tributyl)ammonium chloride. The experimental results are consistent with a catalytic cycle based on an electrophilic palladation pathway at the 3-position of 1-indolyl potassium salts.
Subject(s)
Bromides/chemistry , Carbon/chemistry , Hydrogen/chemistry , Indoles/chemical synthesis , Nitrogen/chemistry , Palladium/chemistry , Catalysis , Indoles/chemistry , Ligands , Molecular Structure , StereoisomerismABSTRACT
4(5)-aryl-1H-imidazoles can be efficiently and selectively prepared by PdCl2(dppf)-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-1H-imidazole with arylboronic acids under phase-transfer conditions. On the other hand, N-unprotected 4(5)-aryl-1H-imidazoles can undergo highly selective Pd(OAc)2-catalyzed and CuI-mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-1H-imidazoles in modest to good yields. No N-arylation byproducts are observed under the experimental conditions used to prepare 2,4(5)-diaryl-1H-imidazoles.
Subject(s)
Imidazoles/chemical synthesis , Palladium/chemistry , Catalysis , Imidazoles/chemistry , Molecular StructureABSTRACT
The in vitro antitumor activity of novel combretastatin-like 1,5- and 1,2-diaryl-1H-imidazoles was evaluated against the NCI 60 human tumor cell lines panel. Compounds 2d and 2g proved to be more cytotoxic than CA-4 in tests involving their evaluation over a 10(-4)-10(-8) range. Docking experiments showed a good correlation between the MG_MID Log GI(50) values of all these compounds and their calculated interaction energies with the colchicine binding site of alphabeta-tubulin.
Subject(s)
Antineoplastic Agents/pharmacology , Imidazoles/chemistry , Stilbenes/pharmacology , Tubulin/drug effects , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor/drug effects , Colchicine/pharmacology , Humans , Imidazoles/pharmacology , Stilbenes/chemistry , Tubulin/metabolismABSTRACT
[reaction: see text] A variety of 1,5-diaryl-1H-imidazoles have been regioselectively synthesized by direct coupling of 1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and a catalyst precursor consisting of a mixture of Pd(OAc)2 and AsPh3. The data obtained in this synthetic study support a reaction mechanism involving an electrophilic attack of an arylpalladium(II) halide species onto the imidazole ring. Interestingly, some imidazole derivatives synthesized in this study have been found to exhibit significant cytotoxic activity against human tumor cell lines.
Subject(s)
Imidazoles/chemical synthesis , Palladium/chemistry , Catalysis , Imidazoles/chemistryABSTRACT
6-Exo-dig and/or 7-endo-dig iodocyclization reactions of functionalized acetylenic derivatives with ICl are disfavored in comparison with the corresponding electrophilic addition reactions providing regioselectively (E)-1-chloro-2-iodoethene derivatives. On the contrary, 6-endo-digand 5-exo-dig iodocyclizations of methyl ynoates with ICl seem to be favored in comparison with the corresponding electrophilic addition reactions.