2-substituted Quinolines Research Articles

Benzoquinone Ligand-Enabled Ruthenium-Catalyzed Deaminative Coupling of 2-Aminoaryl Aldehydes and Ketones with Branched Amines for Regioselective Synthesis of Quinoline Derivatives.

The catalytic system generated in situ from the cationic Ru-H complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1) with 2,3,4,5-tetrachloro-1,2-benzoquinone (L1) was found to be highly effective for promoting the deaminative coupling reaction of 2-aminoaryl aldehydes with branched amines to form 2-substituted quinoline products. The analogous deaminative coupling reaction of 2-aminoaryl ketones with branched amines led to the regioselective formation of 2,4-disubstituted quinoline products. A number of biologically active quinoline derivatives including graveolinine and a triplex DNA intercalator have been synthesized by using the catalytic method.

Synthesis of 2-substituted quinoline derivatives using [RuCl2(p-cymene)]2-ferrocene thioamide catalytic system via acceptorless dehydrogenative coupling

The substituted quinolines were synthesized via acceptorless dehydrogenative coupling (ADC) of 2-aminobenzyl alcohol with ketones/secondary alcohols, which was accomplished using the in situ catalytic activity of [RuCl2(p-cymene)]2 and ferrocene thioamide (Fc-TA) ligands. The catalysis was extended to aromatic and heterocyclic ketones and secondary alcohols, with unsubstituted and chloro‑substituted 2-aminobenzyl alcohols. The Fc-TA ligands (L1-L3) were synthesized, and characterized using spectroscopic techniques such as FT-IR, UV–Vis, NMR and HRMS. The influence of ligands on the catalysis was studied. Overall, the synthesis of quinolines was accomplished with good to moderate yields, via both mono and double dehydrogenation reactions along with hydrogen and water as only by-products.

Ruthenium complexes of redox non-innocent aryl-azo-oximes for catalytic α-alkylation of ketones and synthesis of 2-substituted quinolines

In this work we demonstrated the synthesis, characterisation and catalytic applications of Ru(ii)–azooximato complexes. This is the first report where arylazooximato complexes of a transition metal are used in catalytic C–C bond formation reactions.

Lewis acid-mediated modular route to the synthesis of 3-substituted quinolines from 2-aminobenzyl alcohols and enamine(one)s

A Lewis acid-mediated modular synthesis of 3-substituted quinolines bearing electron-withdrawing groups from readily available 2-aminobenzyl alcohols and N,N′-dimethylenamine(one)s is described.

Non-Friedländer Route to Diversely 3-Substituted Quinolines through Au(III)-Catalyzed Annulation Involving Electron-Deficient Alkynes.

Gold(III)-catalyzed annulation of electron-deficient alkynes and 2-amino-arylcarbonyls provides general modular one-step access to a broad scope of quinoline products. This highly selective reaction is a useful alternative to the classic Friedländer synthesis, which requires harsh reaction conditions. In contrast, the developed method works under relatively mild PicAuCl2-catalyzed conditions and exhibits a high functional group tolerance (40 examples; yields of ≤96%). Another feature of the developed approach is a versatility toward other electron-deficient alkynes. Alkynylsulfones, alkynylcarbonyls, alkynylphosphonates, propiolonitriles, and trifluoromethylated alkynes can be used as the starting materials for the preparation of quinolines diversely substituted at position 3. On the basis of experimental data, we proposed a reaction mechanism in which gold(III) functions as a strong electrophilic activator of the C≡C bond and the carbonyl group. The synthetic potential of the presented method is additionally illustrated by practical postmodifications of the obtained compounds, including a two-step synthesis of interpirdine, a potent drug candidate.

Friedländer-Type Reaction of 4-Cholesten-3-one with 2′-Aminoacetophenone: Angular versus Linear Quinoline-Fused Steroids

To optimize the experimental conditions used for the Friedländer-type condensation, an angular fused 4-substituted quinoline steroid has been obtained in very high yield and regioselectivity using readily available 4-cholesten-3-one and 2′-aminoacetophenone. Moreover, by varying the reaction conditions and the catalyst, the corresponding linear regioisomer was also achieved with an acceptable isolated yield and high chemoselectivity. Both structures have been definitively elucidated via 2D-NMR and fully characterized.

Synthesis and antitubercular activity of novel 4-arylalkyl substituted thio-, oxy- and sulfoxy-quinoline analogues targeting the cytochrome bc1 complex

A library of 4-substituted quinolines was synthesised based on the structural features of the privileged 4-(benzylthio)-6-methoxy-2-methylquinoline scaffold. Quinoline-based chemical probes have proven to be effective anti-tuberculosis agents with the ability of inhibiting components of Mycobacterium tuberculosis (MTB) respiratory chain including the b subunit of the cytochrome bc1 complex. Novel 4-(arylalkyl)-thio, -oxy and sulfoxy-quinoline analogues were tested for their ability to inhibit the growth of MTB H37Rv and QcrB mutant strains, and the compounds mode of action was investigated. Members of the 4-subtituted thio- and sulfoxyquinoline series exhibited significant growth inhibitory activity in the high nanomolar range against wild-type MTB and induced depletion of intracellular ATP. These probes also showed reduced potency in the QcrB T313I mutant strain, thus indicating the cytochrome bc1 oxidase complex as the molecular target. Interestingly, new 4-(quinolin-2-yl)oxy-quinoline 4i was more selective for the QcrB T313I strain compared to the wild-type strain.

Mn(OAc)3-Mediated One-Pot Condensation-Oxidative Annulation of 2-Alkynylanilines and 1,3-Ketoesters: Synthesis of 2-Substituted Quinolines.

A general protocol for oxidative annulation was developed for the preparation of 2-methyl-3,4-diacylquinolines directly from 2-alkynylanilines and 1,3-ketoesters. The reactions were mediated by Mn(OAc)3 in acetic acid at room temperature, which led to the desired quinoline products in one-pot in low to good overall yields on a wide range of substrates. The current method was convenient to conduct and proceeded under mild conditions in short reaction times.

A Pummerer Reaction-Enabled Modular Synthesis of Alkyl Quinoline-3-carboxylates and 3-Arylquinolines from Amino Acids.

Concise synthesis of functionalized quinolines has received continuous research attention owing to the biological importance and synthetic potential of bicyclic N-heterocycles. However, synthetic routes to the 2,4-unsubstituted alkyl quinoline-3-carboxylate scaffold, which is an important motif in drug design, remain surprisingly limited, with modular protocols that proceed from readily available materials being even more so. We herein report an acidic I2-DMSO system that converts readily available aspartates and anilines into alkyl quinoline-3-carboxylate. This method can be extended to a straightforward synthesis of 3-arylquinolines by simply replacing the aspartates with phenylalanines. Mechanistic studies revealed that DMSO was activated by HI via a Pummerer reaction to provide the C1 synthon, while the amino acid catabolized to the C2 synthon through I2-mediated Strecker degradation. A formal [3 + 2 + 1] annulation of these two concurrently generated synthons with aniline was responsible for the selective formation of the quinoline core. The synthetic utility of this protocol was illustrated by the efficient synthesis of human 5-HT4 receptor ligand. Moreover, an unprecedented chemoselective synthesis of 2-deuterated, 3-substituted quinoline, featuring this reaction, has been established.

Three-Component Synthesis of 2-Substituted Quinolines and Benzo[f]quinolines Using Tertiary Amines as the Vinyl Source.

A metal-free method for the construction of 2-substituted quinolines and benzo[f]quinolines from aromatic amines, aldehydes, and tertiary amines has been demonstrated. Cheap and readily available tertiary amines acted as the vinyl source. A new pyridine ring was selectively formed via [4 + 2] condensation that was promoted by ammonium salt under neutral conditions and an oxygen atmosphere. This strategy provided a new route for the preparation of various quinoline derivatives with different substituents at the pyridine ring, which provides the possibility of further modification.

Copper-Catalyzed Decarboxylative Cascade Cyclization for the Synthesis of 2-Arylquinolines

AbstractAn efficient copper-catalyzed intermolecular decarboxylative cascade cyclization has been developed that uses readily accessible starting materials and less-expensive reagents. A one-pot reaction of an aryl aldehyde, an aniline, and acrylic acid permits the direct synthesis of 2-substituted quinolines through the sequential formation of C–N and C–C bonds. Furthermore, the three-component, one-pot, domino strategy features promising chemo- and regioselectivity and also tolerates a wide variety of substrates with excellent functional-group tolerance, high yields, a radical reaction pathway, and aerobic reaction conditions.

Tertiary amines as a C1 synthon: metal-free synthesis of quinolines and 2-substituted quinolinesvia[3+2+1] aerobic cyclization and C–N bond cleavage

An I2-mediated aerobic cyclization reaction of anilines, alkynes, and tertiary amine has been reported. In this protocol, a novel strategy for the synthesis of quinolines using tertiary amines as a C1 synthonviaC–N bond cleavage.

Toxicity and antioxidant activity of 4-hydrazinoquinoline derivatives

Annotation. 4-hydrazinoquinoline derivatives have a wide pharmacological potential. The study of their biological properties showed that they have not only antimalarial, antituberculosis, antiviral activity, but also are good antioxidants. First of all, the toxicity of investigated compounds has been evaluated in silico and in vivo. Software solutions were used for building “structure-toxicity” models and predicting LD50 with the help of GUSAR (Germany), TEST (USA) models. Experimental studies were carried out on 64 white mice without a breed of both sexes weighing 16-24 g. Derivatives of 4-hydrazinoquinoline are classified as low and moderately toxic compounds. Antioxidant activity was investigated on 10 4-substituted quinoline compounds and compared with reference drugs. For the research we used the native material – ejaculates of fertile men (normozoospermia). For this purpose, the indicators of the standard spermogram were previously evaluated according to generally accepted methods in accordance with WHO criteria. Oxidative stress (OS) was created in cells with the help of 3% hydrogen peroxide. To protect against OS caused by hydrogen peroxide, the studied compounds and comparative drugs with AO properties (AK and ACC) were used. The obtained results were processed using the program “STATISTICA® for Windows 6.0” (StatSoft Inc, No. АХХР712D833214FAN5) by methods of variational statistics using the Student’s t-test. Investigating the average speed of motile spermatozoa, it was found that compounds with residues of acetic and pentanedioic acids exceeded the comparison drugs. (Е)-2-(2-(7-chloroquinolin-4-yl)hydrazono)acetic acid demonstrated a stronger effect on 8-10 % than the comparative drug ACC. Disodium (Е)-2-(2-(2-methylquinolin-4-yl)hydrazono)pentanedioate has an advantage over the level of action of AA by 15%. Derivatives of (2-(quinolin-4-yl))hydrazono)carboxylic acids in the conditions of H2O2-induced OS were generally inferior to comparison drugs AA and ACC. These results demonstrate that derivatives of (2-(quinolin-4-yl))hydrazono)carboxylic acids exhibit favorable antioxidant properties and are promising protectors of spermatozoa in OS conditions. The studied series of quinoline derivatives requires both further in-depth studies of the mechanisms of AO protection and favorable structural modifications in this series.

Spotlight on 4-substituted quinolines as potential anti-infective agents: Journey beyond chloroquine.

Continued emerging resistance of pathogens against the clinically approved candidates and their associated limitations continuously demandnewer agents having better potency with a more suited safety profile. Quinoline nuclei containing scaffolds ofnatural and synthetic origin have been documented for diverse types of pharmacological activities, and a number of drugs are clinically approved. In the present review, we unprecedentedly covered the biological potential of 4-substituted quinoline and elaborated a rationale for its special privilege to afford the significant number of approved clinical drugs, particularly against infectious pathogens. Compounds with 4-substituted quinoline are well documented for antimalarial activity, but in the last two decades, they have been extensively explored for activity against cancer, tuberculosis, and several other pathogens including viruses, bacteria, fungi, and other infectious pathogens. In the present study, the anti-infective spectrum of this scaffold is discussed against viruses, mycobacteria, malarial parasites, and fungal and bacterial strains, along with recent updates in this area, with special emphasis on the structure-activity relationship.

Synthesis of Indenoquinolinones and 2-Substituted Quinolines via [4 + 2] Cycloaddition Reaction.

We have reported a metal-free protocol for the synthesis of indenoquinolinones and 2-substituted quinolines via [4 + 2] cycloaddition reaction using readily available 2-aminobenzaldehydes and ketones as starting materials. Different quinoline derivatives can be selectively synthesized by changing the type of ketones. O2 and dimethyl sulfoxide (DMSO) as co-oxidants play an important role in the synthesis of indenoquinolinones. This condensation/oxidation strategy involves the formation of C-N, C-C, and C-O bonds, with the advantages of high yields and a broad substrate range.

Cytotoxic activity of 7-R-4-substituted quinoline

Annotation. Quinoline derivatives are important compounds for chemical synthesis and the development of new drugs and pesticides. The practical application of a number of substances with a quinoline heterocycle in medical practice and agriculture is well known. Quinoline compounds exhibit a wide range of biological effects, including cytotoxic activity. Phytotoxic (cytotoxic) activity of 15 4-substituted quinoline derivatives were studied and compared with reference drugs. 7-R-4-substituted quinoline derivatives were tested by root test on Cucumis sativus L. seedlings at different concentrations. Distilled water was used as reference in the control experiment. During the experiment, all factors were taken into account to create equal conditions for all studied elements. The obtained results were processed using the program “STATISTICA® for Windows 6.0” (StatSoft Inc, No. АХХР712D833214FAN5) by methods of variational statistics using the Student’s t-test. 7-R-4-substituted quinoline derivatives turned out to be predominantly cytotoxic compounds, that corresponds to the “structure-action” dependence between the structure of investigated compounds and their biological activity. All tested compounds have a pronounced phytotoxic effect at the concentration of 500 μg/ml. The most pronounced cytotoxic effect was recorded among the (heteryl)cysteamine derivatives – β-(quinolin-4-yl)cysteamine dihydrochloride, β-(7-chloroquinolin-4-yl)cysteamine dihydrochloride, 3-((7-chloroquinolin-4-yl)thio)propanoic acid hydrochloride. Derivatives of (heterylthio)acetic acids have shown growth-promoting effects at low concentrations. Thus, 2-(quinolin-4-ylthio)- and 2-(7-chloroquinolin-4-ylthio) acetic acids have shown the most active effect (50-250% compared to control group) at concentrations of 1-20 μg ml. Sodium 3-((7-chloroquinolin-4-yl)thio)propanoate has indicators that exceed the control by 7-60%, with the most effective growth of the main root of seedlings by 30% among all studied substances at the concentration of 100 μg/ml compared to control group. Some compounds have cytotoxic activity that can be used in crop production as growth regulators of agricultural plants.

Cp*Co(III)-Catalyzed Selective C8-Olefination and Oxyarylation of Quinoline N-Oxides with Terminal Alkynes.

Herein we report Cp*Co(III)-catalyzed site-selective (C8)-H olefination and oxyarylation of quinoline N-oxides with terminal alkynes. The selectivity for C8-olefination and oxyarylation is sterically and electronically controlled. In the case of quinoline N-oxides (unsubstituted at the C2 position), only the olefination product was obtained irrespective of the nature of the alkynes. In contrast, oxyarylation was observed exclusively when 2-substituted quinoline N-oxides were reacted with 9-ethynylphenanthrene. However, alkynes with electron-withdrawing groups provided only olefination products with 2-substituted quinoline N-oxides. The developed strategy allowed a facile functionalization of quinoline N-oxides bearing natural molecules and an estrone-derived terminal alkyne to deliver the corresponding olefinated and oxyarylated products. To understand the reaction mechanism, control experiments, deuterium-labeling experiments, and kinetic isotope effect (KIE) studies were performed.

Exploration of Isoxazole-Carboxylic Acid Methyl Ester Based 2-Substituted Quinoline Derivatives as Promising Antitubercular Agents.

In pursuit of potent anti-TB agents active against drug resistant tuberculosis (DR-TB), herein we report synthesis and bio-evaluation of a new series of isoxazole-carboxylic acid methyl ester based 2-substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non-tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5-8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR-Mtb) found hit compound displaying promising potency (MIC 1-4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug-susceptible Mtb (MIC 0.12 μg/mL) and drug-resistant Mtb (MIC 0.25-0.5 μg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti-TB candidate.

Discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) and analogs as small molecule Nav1.7/ Nav1.8 blockers for the treatment of pain

The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC50 value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.