ABSTRACT
The crystal structure of tetrazepam, a benzodiazepine derivative formerly used for its muscle relaxant properties, has been solved and found to be monoclinic, space group P21/c, with lattice parameters a=12.7386(7)Å, b=11.3774(7)Å, c=10.3084(7)Å, ß=103.175(5) and Vunit-cell=1454.69(16) Å3 at room temperature (293K) with Z=4 molecules in the unit-cell. A network of weak hydrogen bonds involving aliphatic hydrogen atoms plays an important role in the formation of this structure.
Subject(s)
Benzodiazepines/chemistry , Hydrogen Bonding , Muscle Relaxants, Central/chemistry , Crystallization , Crystallography, X-Ray , Hydrogen/chemistry , Models, Molecular , Temperature , X-Ray DiffractionABSTRACT
An efficient method for regiocontrolled functionalization of 2,3-dihalogenoimidazo[1,2-a]pyridine was developed. This sequence allowed the selective introduction of aryl, heteroaryl, alkyl and alkynyl substituents at both 2- and 3-positions, by using Suzuki-Miyaura and Sonogashira cross-coupling reactions. A library of compounds diversely substituted on 2- and 3-positions can be easily prepared from a common, stable and easily accessible starting material.
ABSTRACT
Heterocyclization of functionalized vinylic derivatives of imidazo[1,2-a]pyridines was explored experimentally and theoretically using semiempirical AM1 and ab initio methods. A range of functionalized vinylic derivatives (azido, amino, and carbodiimide groups) were prepared for conversion into pyrroloazaindoles 19-22, imidazo[1,x]-, (x = 5, 6, 7, 8), [2,6]-, and [2,7]naphthyridines 28-30, 35-38 by thermal reaction. In the case of vinylic groups in the 5 position, peri annulation also was observed. The experimental and theoretical data are compared and discussed.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Pyridines/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Humans , Models, Molecular , Neurodegenerative Diseases/drug therapyABSTRACT
Ten 2-aryl or heteroaryl-3-nitrosoimidazo[1,2-a]pyridine derivatives were synthesised as potential antiretroviral agents. The new compounds were characterized by elemental analysis, 1H NMR, and by crystallography for (14). The compounds were devoid of any activity against HIV-1 or HIV-2.
Subject(s)
Anti-HIV Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Nitroso Compounds/chemical synthesis , Nitroso Compounds/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Retroviridae/drug effects , Cells, Cultured , Crystallography, X-Ray , Humans , Magnetic Resonance SpectroscopyABSTRACT
The solution structure of the complex formed between d(CGATCG)(2) and 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol, a new antitumor drug under design, has been resolved using NMR spectroscopy and restrained molecular dynamic simulations. The drug molecule intercalates between each of the CpG dinucleotide steps with its side chain lying in the minor groove. Analysis of NMR data establishes a weak stacking interaction between the intercalated ligand and the DNA bases; however, the drug/DNA affinity is enhanced by a hydrogen bond between the hydroxyl group of the end of the intercalant side chain and the amide group of guanine G6. Unrestrained molecular dynamic simulations performed in a water box confirm the stability of the intercalation model. The structure of the intercalated complex enables insight into the structure-activity relationship, allowing rationalization of the design of new antineoplasic agents.
Subject(s)
Antineoplastic Agents/chemistry , DNA/chemistry , Intercalating Agents/chemistry , Nucleic Acid Heteroduplexes/chemistry , Oligonucleotides/chemistry , Purines/chemistry , Binding Sites , Deoxyribose/chemistry , Imidazoles/chemistry , Nuclear Magnetic Resonance, Biomolecular/methods , Nucleic Acid Conformation , Organophosphates/chemistry , Protons , Pyridines/chemistry , Solutions , ThermodynamicsABSTRACT
The synthesis and antiviral activity of original dibromoimidazo[1,2-a]pyridines bearing a thioether side chain are reported. Molecular modeling was used to identify biophoric structural patterns that are common to 16 compounds. Structure-activity relationship (SAR) studies identified hydrophobicity (logP) as the most important factor for activity. From these SAR studies, the antiviral activity could be predicted.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Giant Cells/drug effects , Giant Cells/virology , HIV-1/drug effects , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Quantitative Structure-Activity RelationshipABSTRACT
Two pyrido[1,2-e]purins with different side chain lengths have been synthesized to test their ability to intercalate inside DNA. The interactions of these drugs with synthetic oligodeoxy nucleotide d(CGATCG)2 have been studied with 1H and 31P NMR spectroscopy experiments. Molecule 1, rather amphiphilic (Log(P) = 1.3, due to its hydroxypropyl side chain) can intercalate GC sites of the mini helix, under a fast exchange mechanism and a 2:1 stoechiometry. The presence of a six methylen side chain in 2 (hydroxyhexyl side chain) is responsible for a relatively poor solubility of this molecule in water (log P = 2.3). Binding, rather than intercalation, of 2 to the external GC pairs is observed, severely limited by the formation of aggregates. Models for the intercalation of 1, are proposed using energy minimizations and Molecular Dynamics (MD) calculations subject to restraints from experimental nOe connectivities. Simulations and experiments both indicate fast exchange of 1 in its intercalation site.
Subject(s)
Intercalating Agents/chemical synthesis , Purines/chemical synthesis , DNA/drug effects , Hydrogen Bonding , Intercalating Agents/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Oligonucleotides/chemical synthesis , Oligonucleotides/pharmacology , Protons , Purines/chemistry , SolventsABSTRACT
This work reports the synthesis and the antiviral activities of 3-benzamido, 3-phenylureido and 3-phenylthioureido derivatives in the imidazo[1,2-a]pyridine series. The structure was proven by NMR spectroscopy. The synthesized compounds were evaluated against a large number of viruses. The 3-phenylthioureido derivative 7 showed moderate activity against human cytomegalovirus (HCMV) in vitro. The crystallographic data for 8 are also reported and explain the absence of activity against human immunodeficiency virus (HIV).
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Thiourea/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Cells, Cultured , Crystallography, X-Ray , Cytomegalovirus/drug effects , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/pharmacology , Viral Plaque AssayABSTRACT
The influence of base and solvent in Suzuki cross-coupling reaction on various 2-substituted-3-iodoimidazo[1,2-a]pyridines was reported. The reactivity was largely influenced by nature of the substituent. Optimized yields and shortened times of reaction were obtained using strong bases in DME.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Boronic Acids/chemistry , Cyclooxygenase Inhibitors/chemistry , Pyridines/chemistryABSTRACT
From a pharmacophore model of bicyclic heterocycles as aromatase inhibitors we have designed three series of imidazo[1,2-a]pyridine derivatives. The synthesis and the spectroscopy determination of various compounds are reported. The crystal data of one of these compounds (10b) was obtained. The aromatase inhibition potency was evaluated in vitro and no activity was found.
Subject(s)
Aromatase Inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Molecular Conformation , Pyridines/chemistry , Pyridines/pharmacology , X-Ray DiffractionABSTRACT
From the latex of Lapsana communis L. subps. communis, five guaianolide glycosides were identified: crepiside E, tectoroside and three new ones: 3-O-beta-D-glucopyranosyl-8-O-beta-acetyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-4(15),10(14),11(13)-triene-6,12-olide, 3-O-beta-D-glucopyranosyl-8-O-beta-acetyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3(4),10(14), 11(13)-triene-15-methyl-6,12-olide, and 3-O-beta-glucopyranosyl-8-O-beta-(4-hydroxyphenyl)-lactyl-1 alpha H,5 alpha H,6 beta H,7 alpha H-guai-3(4),10(14),11(13)-triene-15-methyl-6,12-olide. Their structures were established by spectroscopic methods.
Subject(s)
Asteraceae/chemistry , Glycosides/isolation & purification , Lactones/chemistry , Sesquiterpenes/chemistry , Animals , Drug Screening Assays, Antitumor , Glycosides/chemistry , Glycosides/pharmacology , Leukemia L1210/pathology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular StructureABSTRACT
Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. [2] and [3], on the other hand, have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of [2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site.
Subject(s)
Antineoplastic Agents/chemical synthesis , Oligonucleotides/metabolism , Purines/chemistry , Purines/metabolism , Sulfonamides/chemistry , Sulfonamides/metabolism , Animals , Cell Line , Intercalating Agents/metabolism , Kinetics , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Muscle, Skeletal/metabolism , Mutagenicity Tests , Nucleic Acid Conformation , Protons , Purines/chemical synthesis , Sulfonamides/chemical synthesisABSTRACT
The anticancer activity of 4-methylaminopyridol[1,2-e]purine 6a, 4-(piperidin-1-yl)pyrido[1,2-e]purine 7a and their 7-methyl derivatives 6b, 7b was investigated against the human MCF7 cancer cell line in vitro. The sensitive cell line showed a range of sensitivities to 6a, 6b, 7a, 7b (IC50: 1.6 to 7.2 x 10(-4) M) and sensitivity to doxorubicin (IC50: 7.5 x 10(-7) M). A resistant cell line with the multidrug resistant phenotype was sensitive to these derivatives (IC50: 1.8 to 6.7 x 10(-4) M), doxorubicin (IC50: 5 x 10(-5) M) and drug activity seems to be not affected by MDR resistance. Our data show that 6a, 6b, 7a and 7b appear to exert a low cytotoxicity on sensitive and MDR resistant MCF7 human cancer cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Resistance, Multiple/genetics , Purines/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antibiotics, Antineoplastic/pharmacology , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Cell Line , Coloring Agents , Doxorubicin/pharmacology , Humans , Purines/pharmacology , Tetrazolium Salts , Thiazoles , Tumor Cells, CulturedABSTRACT
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure-activity relationship is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Cytomegalovirus/drug effects , Drug Evaluation, Preclinical , HeLa Cells , Herpesvirus 3, Human/drug effects , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity Relationship , Vero CellsABSTRACT
Interactions of three pryridopurines differing by their side chain, -SCH2-Phe [1], -SCH2-CHOH-CH3 [2], and -SCH2-CHOH-CH2OH [3], with model membranes were studied by proton, phosphorus and carbon NMR. Their incorporation in phospholipid multilayers induced a membrane rigidification without altering ther main bilayer structure nor the phase transition. Depending on the more or less amphiphilic properties, these molecule have different behavior when included in small unilamellar vesicles: hydrophobic [1] is found in the deepest part of the membrane, while [2] lies at an intermediate location in the layer. [3] is more hydrophilic: its aromatic moiety is in the intermediate part of the membrane whereas the side chain is found oriented towards the superficial part of the layer. Furthermore, the amphiphilic molecule [2] has transmembrane transport abilities when in the presence of large unilamellar vesicles.
Subject(s)
Lipid Bilayers/chemistry , Phospholipids/chemistry , Purines/chemistry , Pyridines/chemistry , Kinetics , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular/methods , Structure-Activity RelationshipABSTRACT
The synthesis and the antiviral activities of C-3 acyclic nucleoside analogues of imidazo[1,2-a]pyridine and pyrimidine are reported. From these compounds, 20, 21, 22, 23, 28, and 34 showed a specific activity against cytomegalovirus and/or varicella-zoster virus.
Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Pyridines/chemistry , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Antiviral Agents/pharmacology , Chlorocebus aethiops , HeLa Cells , Humans , Nucleosides/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured , Vero CellsABSTRACT
Three potentially antiviral imidazo[1,2-a]pyridine derivatives of increasing hydrophilicity were tested in their interactions with model membranes and synthetic oligonucleotides. It was shown that the most hydrophobic derivative [1], located in the depth of the bilayer only induces minor membrane damages. The molecule [2], only poorly hydrophobic, integrates also the bilayer in the medium part of the chains while the most hydrophilic [3] exhibits fluidizing and slightly detergent properties. In the presence of synthetic oligonucleotide ACATGT no intercallation of the three derivatives was evidenced. By considering their antiviral activity in the absence of evident mitogenic properties, another mechanism of action was proposed.
Subject(s)
Antiviral Agents/chemistry , Imidazoles/chemistry , Pyridines/chemistry , Lipid Bilayers/chemistry , Magnetic Resonance Spectroscopy , Membranes, Artificial , Oligonucleotides/chemistryABSTRACT
Crucial conditions for the pharmacological use of active compounds are their ability to cross the biological barriers and reach their intracellular target. In the case of two antiviral pyridopurine derivatives, 1 and 2, this included essentially the membranes and the nucleic acids. Thus the interactions of 1 and 2 with model membranes and oligonucleotides were studied using NMR spectroscopy. It was found that these hydrophobic molecules can be incorporated into the model membranes at the terminal methyl group level, inducing dynamic perturbations in the bilayer. In the presence of the synthetic oligonucleotide ACATGT, both molecules can intercalate aspecifically in AT and GC systems. Inclusion complexes of 1 and 2 beta-cyclodextrins with a 1:1 stoichiometry, were also prepared. This led to to propose two galenic forms 1 and 2, i.e. included in phospholipid vesicles in the form of a beta-cyclodextrin complex