On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Recent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.Fundacao para a Ciencia e Tecnologia (FCT - Portugal) [UID/Multi/04326/2013]; QREN-COMPETE-UE; CCMAR; FCT [SFRH/BD/81821/2011, RECI/BBB-BQB/0230/2012, UI0313/QUI/2013, UID/FIS/04564/2016]; FEDER/COMPETE-UE; [PTDC/QEQ-QFI/3284/2014 - POCI-01-0145-FEDER-016617]info:eu-repo/semantics/publishedVersio

Scientific Opinion on the re-evaluation of Quinoline Yellow (E 104) as a food additive:Question No EFSA-Q-2008-223

The Panel on Food Additives and Nutrient Sources added to Food provides a scientific opinion re-evaluating the safety of Quinoline Yellow (E 104). Quinoline Yellow has been previously evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1975, 1978 and 1984, and the EU Scientific Committee for Food (SCF) in 1984. Both committees established an Acceptable Daily Intake (ADI) of 0-10 mg/kg body weight (bw). Studies not evaluated by JECFA and the SCF included a chronic toxicity and carcinogenicity study with a reproductive toxicity phase in rats and a study on behaviour in children by McCann et al. from 2007. The latter study concluded that exposure to a mixture of colours including Quinoline Yellow resulted in increased hyperactivity in 8- to 9-years old children. The Panel concurs with the conclusion from a previous EFSA opinion on the McCann et al. study that the findings of the study cannot be used as a basis for altering the ADI. The Panel notes that Quinoline Yellow was negative in in vitro genotoxicity as well as in long term carcinogenicity studies. The Panel concludes that the currently available database on semi-chronic, reproductive, developmental and long-term toxicity of Quinoline Yellow, including a study in rats not apparently taken into consideration by JECFA or the SCF, provides a rationale for re-definition of the ADI. Using the NOAEL of 50 mg/kg bw/day provided by the chronic toxicity and carcinogenicity study with a reproductive toxicity phase carried out in rats and applying an uncertainty factor of 100 to this NOAEL, the Panel establishes an ADI of 0.5 mg/kg bw/day. The Panel notes that at the maximum levels of use of Quinoline Yellow, refined intake estimates are generally well over the ADI of 0.5 mg/kg bw/day

A New synthesis of triazolo[4,5-g]quinolines and unexpected ring reduced products by treatment with hydrazine hydrate

A new synthesis of the linear heterocycle 4-chloro-1H-triazolo[4,5-g]quinoline by reduction of the novel compound 4-chloro-1H-triazolo[4,5-g]quinoline-1-oxide is reported. Treatment of the latter with hydrazine hydrate in ethanol in a sealed steel vessel in the presence or not of palladised charcoal, under various conditions of both time and temperature, afforded some derivatives of both ring reduction and ring construction

Intramolecular Imino Diels-Alder Reaction: Progress toward the Synthesis of Uncialamycin

We herein described an intramolecular imino Diels-Alder reaction promoted with BF3.OEt2/DDQ affording substituted quinolines. Using this procedure, we prepared the chiral quitioline moiety of the uncialamycin, a new enediyne natural product

Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids

This is the pre-peer reviewed version of the following article: Synthesis, In Silico Studies, Antiprotozoal and Cytotoxic Activities of Quinoline‐Biphenyl Hybrids, which has been published in final form at https://doi.org/10.1002/slct.201903835. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThe synthesis, in silico studies, antiprotozoal and cytotoxic activities of eleven quinoline‐biphenyl hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against Plasmodium falciparum, and amastigotes forms both Leishmania (V) panamensis and Trypanosoma cruzi. Cytotoxicity was evaluated against human U‐937 macrophages. 8‐phenylquinoline (4 a) showed similar activity than meglumine antimoniate and 4‐(quinolin‐8‐yl)phenol (4 b) exhibited an activity similar to that of benznidazole. 8‐(3,4‐dimethoxyphenyl) quinoline (4 k) showed the best activity against P. falciparum. Although these compounds were toxic for mammalian U‐937 cells, however they may still have potential to be considered as candidates for drug development because of their antiparasite activity. Molecular docking was used to determine the in silico inhibition of some of the designed compounds against PfLDH and cruzipain, two important pharmacological targets involved in antiparasitic diseases. All hybrids were docked to the three‐dimensional structures of PfLDH and T. cruzi cruzipain as enzymes using AutoDock Vina. Notably, the docking results showed that the most active compounds 4‐(quinolin‐8‐yl)phenol (4 b, CE50: 11.33 μg/mL for T. cruzi) and 8‐(3,4‐dimethoxyphenyl) quinoline (4 k, CE50: 8.84 μg/mL for P. falciparum) exhibited the highest scoring pose (−7.5 and −7.7 kcal/mol, respectively). This result shows a good correlation between the predicted scores with the experimental data profile, suggesting that these ligands could act as competitive inhibitors of PfLDH or T. cruzi cruzipain enzymes, respectively. Finally, in silico ADME studies of the quinoline hybrids showed that these novel compounds have suitable drug‐like properties, making them potentially promising agents for antiprotozoal therapy

Enantioselective hydrogenation of activated ketones in the presence of Pt–cinchona catalysts. Is the proton transfer concept valid?

Experimental evidences related to the proton transfer in the catalytic system Pt-Cinchona alkaloids for enantioselective hydrogenation of activated ketones were collected and analyzed. Both new and earlier results indicate that in aprotic media direct transfer of proton from platinum to the substrate with the involvement of quinuclidine nitrogen as a general rule can be questioned

A ratiometric Al³⁺ ion probe based on the coumarin-quinoline FRET system

A coumarin-quinoline based fluorescence resonance energy transfer (FRET) system (TCQ) has been synthesized and employed as a ratiometric fluorescence probe. The selective fluorescent response of the probe TCQ toward Al³⁺ was devised by employing a quinoline moiety as a FRET energy donor with a coumarin moiety as an energy acceptor. The quinoline emission at 390 nm decreased and the coumarin emission at 480 nm increased concurrently on addition of Al³⁺ under excitation wavelength at 253 nm. The TCQ probe exhibited high selectivity for Al³⁺ as compared to other tested metal ions and the ratiometric sensing of Al³⁺ was determined by plotting the fluorescence intensity ratio at 480 nm and 390 nm versus Al³⁺ ion concentration. Moreover, test strips based on TCQ were fabricated, which were found to act as a convenient and efficient Al³⁺ ion detection kit. Furthermore, this system has been used for imaging of Al³⁺ in living cells

Draft Genome Sequence of Rhodococcus sp. Strain ATCC 49988, a Quinoline-Degrading Bacterium.

We report here the 4.9-Mb genome sequence of a quinoline-degrading bacterium, Rhodococcus sp. strain ATCC 49988. The draft genome data will enable the identification of genes and future genetic modification to enhance traits relevant to heteroaromatic compound degradation

Synthesis, anti-tuberculosis activity and QSAR study of 2,4-diarylquinolines and analogous polycyclic derivatives

The multicomponent syntheses of 2,4-di-aryl-quinolines and analogous polycyclic derivatives as anti-tuberculosis agents were described. They were prepared via Beyer and Friedländer methods under microwave irradiation in short reaction times and good yields. Several homogeneous and heterogeneous acid catalysts were compared for preparing 2,4-di-arylquinolines and among them trifluoroacetic acid (TFA) reached the higher yields. Two derivatives exhibited activity against Mycobacterium tuberculosis H37Rv (Mtb), underwent additional testing and were considered lead compounds. The synthesis of a series of polycyclic analogous led to six new active compounds and a Quantitative Structure Activity Relationship study (QSAR) study was established.Fil: Muscia, Gisela Celeste. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Carnevale, Juan Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Luczywo, Ayelen. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Victoria Peláez, María. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Rodríguez Ó Toole, Ailen. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Buldain, Graciela Yolanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Casal, Juan José. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Asís, Silvia Elizabeth. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentin