Quinoline Nucleus Research Articles

Synthesis of 5-Iodopyrrolo[1,2-a]quinolines and Indolo[1,2-a]quinolines via Iodine-Mediated Electrophilic and Regioselective 6-endo-dig Ring Closure

The endo-cyclic ring closure of 1-(2-(substituted ethynyl)phenyl)-1H-pyrroles 3a-t and 1-(2-(substituted ethynyl)phenyl)-H-indole 4a-o mediated by Lewis acid (I(2)) under mild conditions afforded substituted 5-iodopyrrolo[1,2-a]quinolines 5a-t and 5-iodoindolo[1,2-a]quinolines 6a-o in good to excellent yields. The reaction shows selective C-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized product. Iodo derivatives of pyrrolo- and indoloquinolines allow functional group diversification on the quinoline nucleus, which proves to be highly advantageous for structural and biological activity assessments.

Synthesis and structure of di(2-phenyl-8-quinolyl) diselenide and zinc bis[(2-phenyl-8-quinolyl)selenolate

Di(2-phenyl-8-quinolyl) diselenide [2-(C 6 H 5 )C 9 H 5 NSe] 2 and zinc bis[(2-phenyl-9-quinolyl)selenolate], Zn [2-(C 6 H 5 )C 9 H 5 NSe] 2 , have been synthesized. The molecular and crystal structure of the compounds were determined by X-ray structural analysis. The structures of the 2-phenyl-8-quinolylselenol ligand in the molecules of di(2-phenyl-8-quinolyl) diselenide and in the intracomplex compound of zinc are compared. The effect of the phenyl group in position 2 of the quinoline nucleus on the formation of the molecules and their packing in the crystal structure is discussed.

Predicting anti-cancer activity of quinoline derivatives: CoMFA and CoMSIA approach

The 3D quantitative structure-activity relationships of 31 quinoline nuclei containing compounds and their biological activity have been investigated to establish various models. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies resulted in reliable and significant computational models. The obtained CoMFA model showed high predictive ability with q2 = 0.592, r2 = 0.966 and standard error of estimation (SEE) = 0.167, explaining majority of the variance in the data with two principal components. Predictions obtained with CoMSIA steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor fields (q2 = 0.533, r2 = 0.985) showed high prediction ability with minimum SEE (0.111) and four principal components. The information obtained from the CoMFA and CoMSIA contour maps can be utilized for the design and development of topoisomerase-II inhibitors for synthesis.

Photochemical Degradation of Glaphenine Solution

The aim of this work was to study the effect of light on glaphenine stability in solutions. Glaphenine solutions in various solvents, including alcohols, acidic alcohols, water and acidic aqueous media, were exposed to both artificial light source and solar radiation. The photodegradation was followed using different techniques including UV-visible spectrophotometry, spectrofluorometry, mass spectrometry, HPLC and TLC. Studying the effect of solvents on the stability showed that glaphenine is completely stable towards light in water and in acidic media. In neutral alcohols, the rate of photodecomposition was found to increase in the order methanol < ethanol < pentanol < butanol < propanol, which may be explained by solvent-solute interaction and viscous properties of the solvent. Two photodegraded products were separated and identified as a-glycerylanthranilate and 7-chloroquinoline. Drug molecules having particular structures may undergo photodegradation when irradiated with light. This necessitates the testing for photodecomposition in the preformulation stage to safeguard against such deterioration. Factors affecting photodecomposition differ between solid and liquid forms. Consequently, photodecomposed species need to be identified when possible, in solid and solution states. Glaphenine, a-glyceryl N-(7-chloro4-quinolyl) anthranilate, is an analgesic that has been used for the relief of all types of pain. Recently, its use has been limited by the high incidence of anaphylactic reactions. Glaphenine comprises anthranilic and quinoline nuclei, which show instability towards UV or visible radiation in solution (Fujishiro 1960; Stermitz et a1 1970). Glaphenine powder is stable against heat and moisture but undergoes photodegradation when exposed to UV-visible or solar radiation. The decomposition products are similar regardless of the method of radiation used. Two main photodecomposed products were identified as N(7-chloro-4-quinolyl) anthranilic acid and methyl N-(7-chloro-4-quinolyl) anthranilate; intramolecular abstraction leads to the formation of these photodegraded products (Badwan et a1 1992). It is of prime interest to compare the degradation products produced from solid state and those obtained Correspondence: A. A. Badwan, The Jordanian Pharmaceutical Manufacturing Co., PO Box 94, NAOR 11710, Jordan.

Non-peptide NK 1 receptor ligands based on the 4-phenylpyridine moiety

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK 1 receptor ligands 7 has been transformed into either substituted or azole—(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK 1 receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK 1 receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC 50 value of 4.8 nM and was proved to behave as a NK 1 antagonist blocking Sar 9-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [ 11C]CH 3I ( t 1/2 = 20.4 min, β + = 99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity >1 Ci/μmol in order to be used as a radiotracer in next PET studies.

Synthesis and in vitro antimicrobial evaluation of penta-substituted pyridine derivatives bearing the quinoline nucleus

A new series of penta-substituted pyridine derivatives bearing the quinoline nucleus have been synthesized by base-catalyzed cyclocondensation reaction through multi-component reaction (MCR) approach. All the synthesized compounds were subjected to in vitro antimicrobial screening against three Gram positive bacteria (Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae), three Gram negative bacteria (Escherichia coli, Salmonella typhi, Vibrio cholerae), and two fungi (A. fumigatus, Candida albicans). Reviewing the data, majority of the compounds were found to be active against B. subtilis and C. tetani while the most effective compounds 4c and 4e demonstrated MIC 62.5 μg/ml against V. cholerae and E. coli respectively.

Synthesis and antimicrobial activities of novel n-substituted 8-(1-alkyl/alkylsulphonyl/alkoxycarbonyl-benzimidazol-2-ylmethoxy)-5-chloroquinolines

Herein the synthesis of a series of novel 8-(1- alkyl/alkylsulphonyl/alkoxycarbonyl-benzimidazol-2-ylmethoxy)-5- chloroquinoline derivatives is reported. These derivatives were prepared by the condensation of o-phenylenediamine with [(5-chloroquinolin-8- yl)oxy]acetic acid, followed by substitution at nitrogen with different electrophilic reagents in presence of an appropriate base to give a series of nitrogen heterocycles containing the benzimidazole and quinoline nuclei. The structures of the compounds were confirmed based on 1H-NMR, 13CNMR, IR and mass spectral data. Almost all the compounds exhibited promising antibacterial activity against Salmonella typhimurium and Staphylococcus aureus. Some of the compounds showed good antifungal activities against Aspergillus niger but the antifungal activities against Candida albicans were disappointing.

Design, synthesis and biological evaluation of γ-lactam hydroxamate based TACE inhibitors

A new series of γ-lactam hydroxamate based TACE inhibitors was designed mainly by introducing various substitutions at the 2nd position of the quinoline nucleus to achieve high potency and good selectivity towards TACE over matrix metalloproteases (MMPs) and ADAM-10. In ex vivo TNF-α inhibitory activity assays, compounds 11o and 11p were identified as the most potent compounds. The in vitro TACE inhibitory activity, selectivity over MMPs and ADAM-10 and the in vivo TNF-α inhibitory activities of compounds 11o and 11p were assessed and lead compound 11p was identified. Preliminary toxicity and pharmacokinetic (PK) studies were conducted for compound 11p and it showed an improved PK and clean toxicological profile compared to standard compound 1. Altogether, these results demonstrated the discovery of highly potent and selective γ-lactam hydroxamate based TACE inhibitors which show potential for the safe and effective treatment of inflammatory diseases.

Rational Approach to the Synthesis, Evaluation, and 68Ga Labeling of a Novel 4-Anilinoquinoline Epidermal Growth Factor Receptor Inhibitor as a New Imaging Agent That Selectively Targets the Epidermal Growth Factor Receptor Tyrosine Kinase

Certain small-molecule inhibitors that target epidermal growth factor receptor (EGFR), such as Gefitinib, Erlotinib, and Lapatinib, provide a new approach for cancer treatment. In accordance with the pharmacophore model for inhibitor competition at EGFR-binding site, this study proposes a rationalized design for a novel 4-anilinoquinoline EGFR tyrosine kinase inhibitor, [6,7-dimethoxyethoxy]-quinolin-4-yl]-(3-ethynylphenyl)-amine (YCU07). This is the first study to apply ring-closing metathesis toward synthesis of the quinoline nucleus for this 4-anilinoquinoline EGFR inhibitor. YCU07 expressed significant inhibitory activity for EGFR tyrosine kinase in A431 cells, as confirmed by an ABTS microwell peroxidase substrate system read colorimetrically at 405 nm. Injection of (68)Ga-labeled glutamic acid polypeptide (GAP)-YCU07 conjugate in nude mice implanted with A431 was imaged by animal PET camera (LabPET8; Gamma Medica-Ideas) and computed tomography (eXplore Locus; GE Healthcare), to evaluate its biodistribution. (68)Ga-GAP-YCU accumulated in the receptor-positive tumors, with uptake values of 1.50% +/- 0.09% and 2.36% +/- 0.36% of injected activity per gram tissue at 30 and 90 minutes, respectively.

Identification of 4-hydroxyquinolines inhibitors of p300/CBP histone acetyltransferases

We identified a series of 4-hydroxyquinolines bearing a C1 to C15 alkyl chain at the C2 position and a carbethoxy/carboxy group at the C3 position of the quinoline nucleus (MC compounds), endowed with selective inhibitory activity against the p300/CBP HAT enzymes. Enzyme inhibition was investigated using in vitro HAT assays and by western blot analysis of cellular lysates to examine the acetylation levels of histone H3 and α-tubulin. When tested in U937 cells, some compounds displayed pro-apoptotic or cytodifferentiating properties.

Investigations in 2,3′-biquinoline series 24. Synthesis of 3-hetarylquinolines and their 1,4-dihydro derivatives under conditions of the Vilsmeier reaction

Methods have been developed for the synthesis of 2,3′-biquinolines, their 1′,4′-dihydro derivatives, 3-pyrid-2-ylquinolines, and 3-pyrazin-2-ylquinoline based on the interaction of hetarylethylenes and vinyl butyl ether with imidoyl chlorides and Vilsmeier complexes. Using the example of the synthesis of 3-hetarylquinolines and their dihydro derivatives the synthetic possibilities of the Vilsmeier method were shown for creating various bonds in different quinoline nuclei of the bisheterocyclic system.

Colorimetric Discrimination between Important Alkaloid Nuclei Mediated by a Bis-Salphen Chromophore

A new colorimetric method is presented that allows for simple and effective discrimination between (iso)quinoline nuclei pertinent to many alkaloid species. The method is based on the reversible incorporation of Zn2+ ions into a bis-salphen chromophore under aqueous conditions. The metalation process is a function of the stability of the Zn-N (acceptor-donor) interaction and is accompanied by a clear colorimetric response.

Design, synthesis, and structure–affinity relationship studies in NK 1 receptor ligands based on azole-fused quinolinecarboxamide moieties

The substituent in position 2 of the quinoline nucleus of NK 1 receptor ligands 5 has been constrained into different five-membered heterocyclic moieties in order to obtain information on the binding site pocket interacting with this apparently critical portion of ligands 5. This structure–affinity relationship study led to the discovery of novel tricyclic NK 1 receptor ligands 6 showing affinity in the nanomolar range to the sub-micromolar one. The systematic structure variation suggests that electronic features of the tricyclic moiety play a role in modulating the interaction of these amide derivatives with their receptor.

Synthesis and Biological Characterization of Novel 2-Quinolinecarboxamide Ligands of the Peripheral Benzodiazepine Receptors Bearing Technetium-99m or Rhenium

Potential receptor imaging agents based on Tc-99m for the in vivo visualization of the peripheral benzodiazepine receptor (PBR) have been designed on the basis of the information provided by the previously published structure-affinity relationship studies, which suggested the existence of tolerance to voluminous substituents in the receptor area interacting with 3-position of the quinoline nucleus of 2-quinolinecarboxamides 5. In the first step of the investigation, the stereoelectronic features of the above-indicated receptor area were also probed by means of 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide derivatives bearing different substituents on the terminal piperazine nitrogen atom (compounds 6a-f). The structure-affinity relationship data confirmed the existence of a tolerance to bulky lipophilic substituents and stimulated the design of bifunctional ligands based on the 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide moiety (compounds 6h,j,k,m). The submicromolar PBR affinity of rhenium complexes 6j,m suggests that the presence of their metal-ligand moieties with encaged rhenium is fairly compatible with the interaction with the PBR binding site. Thus, in order to obtain information on the in vivo behavior of these bifunctional ligands, (99m)Tc-labeled compounds 6h,k were synthesized and evaluated in preliminary biodistribution and single photon emission tomography (SPET) studies. The results suggest that both tracers do not present a clear preferential distribution in tissues rich in PBR, probably because of their molecular dimensions, which may hamper both the intracellular diffusion toward PBR and the interaction with the binding site.

Reactions of Alkylation of Biologically Interesting Triazolo[4,5-g]quinolines and Triazolo[4,5-g]quinoline-1-oxides with Electrophilic Reagents

- With the aim to improve the biological activities discovered for compounds containing the triazolo[4,5-g]quinoline nucleus, we describe the chemical behaviour of 4-chlorotriazolo[4,5-g]quinolines (la,b) and some its triazolo-N 1 -oxide derivatives (1c-e and II) with electrophilic reagents in order to optimize the synthetic pathways for obtaining both mixtures of N 1,2,3 -alkyl isomers and selectively N 1 -O-alkyl derivatives.

Design, Synthesis, and Preliminary Pharmacological Evaluation of New Quinoline Derivatives as Nicotinic Ligands

A series of nicotinic ligands, carrying a quinoline nucleus, and characterized by a pharmacophoric distance between the quinoline nitrogen (H-bond acceptor) and the cationic nitrogen atoms higher than that proposed in the classical pharmacophoric models, have been synthesized and tested for their affinity for the central nicotinic receptor. The enantiomers of the nicotine analogue 1-methyl-2-pyrrolidinyl-6-quinoline and of its methiodide display enantioselectivity in binding studies, but not when tested in vivo; on alpha7* nicotinic receptor enantioselectivity is inverted with respect to the alpha4beta2* subtype. N,N,N-Trimethyl-4-(quinolin-6-yl)but-3-yn-1-ammonium iodide (3c) and trans-N,N,N-trimethyl-4-(quinolin-6-yl)but-3-en-1-ammonium iodide (4c), showing pharmacophoric distances in the range 8.5-10.4 A, interact with the alpha4beta2* nicotinic receptor with Ki in the microM range; compound 3c shows preference for the alpha7* subtype.

4-Hydroxy-2-quinolones 113. Synthesis and antitubercular activity of N-R-amides of 4-hydroxy-6-methyl-2-oxo-1-propyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid

A preparative method has been developed and the synthesis has been effected of anilides and heterylamides of 4-hydroxy-6-methyl-2-oxo-1-propyl-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid. A comparative analysis has been carried out of the structure and antitubercular properties of the synthesized compounds and their analogs unsubstituted in the quinoline nucleus.

Synthesis, labeling, and biological evaluation of halogenated 2-quinolinecarboxamides as potential radioligands for the visualization of peripheral benzodiazepine receptors

The previous exploration of the structure–affinity relationships concerning 4-phenyl-2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands 6 showed as an interesting result the importance of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus. The subnanomolar PBR affinity shown by N-benzyl-3-chloromethyl- N-methyl-4-phenyl-2-quinolinecarboxamide ( 6b) suggested its chlorine atom to be replaced with other halogens in order to optimize the interaction of the quinolinecarboxamide derivatives with PBR and to develop suitable candidates for positron emission tomography (PET) or single photon emission computed tomography (SPECT) studies. The binding studies led to the discovery of fluoromethyl derivative 6a, which showed an IC 50 value of 0.11 nM and is, therefore, one of the most potent PBR ligands so far described. Fluoromethyl derivative 6a has been labeled with 11C ( t 1/2 = 20.4 min, β + = 99.8%) starting from the corresponding des-methyl precursor ( 14) using [ 11C]CH 3I in the presence of tetrabutylammonium hydroxide in DMF with a 35–40% radiochemical yield (corrected for decay) and 1.5 Ci/μmol of specific radioactivity. Ex vivo rat biodistribution and inhibition (following intravenous pre-administration of PK11195) studies showed that [ 11C] 6a rapidly and specifically accumulated in PBR-rich tissues such as heart, lung, kidney, spleen, and adrenal, and at a lower level in other peripheral organs and in the brain. The images obtained in mouse with small animal YAP-(S)PET essentially confirmed the result of the ex vivo biodistribution experiments. The biological data suggest that [ 11C] 6a is a promising radioligand for peripheral benzodiazepine receptor PET imaging in vivo.

Synthesis and Antimalarial Activity of E‐2‐Quinolinylbenzocycloalcanones.

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Theoretical study on the structures and absorption properties of styryl dyes with quinoline nucleus

The ground-state geometries, the lowest energy transitions and the electronic spectra for a series of styryl dyes with quinoline nucleus have been studied with TD-DFT including SCRF approach. TD-DFT calculations provide a correct description of the UV–Vis spectra of these dye molecules. Moreover, the π → π ∗ type absorption bands of unsubstituted or substituted styrylquinolines are all reasonably well reproduced by TD-DFT at the B3LYP/6-311G ∗∗ level. Compared with our previously reported experimental data, the average relative deviation of λ max is −2.56% in gas phase and −2.48% in methanol solvent.