15644-86-7

Usage

Synthesis Reference(s)

Journal of the American Chemical Society, 71, p. 1906, 1949 DOI: 10.1021/ja01174a002

InChI:InChI=1/C10H8ClNO/c1-6-4-10(13)8-5-7(11)2-3-9(8)12-6/h2-5H,1H3,(H,12,13)

Upstream product

• 4295-37-8 6-chloro-2-methyl-2,3-dihydro-1H-quinolin-4-one 
• 56963-63-4 ethyl 3-(4-chlorophenylamino)crotonate 
• 141-97-9 ethyl acetoacetate 
• 106-47-8 4-chloro-aniline 
• 1392200-83-7 C₁₂H₁₄ClNO₂ 
• 41014-75-9 ethyl 3-((4-chlorophenyl)amino)but-2-enoate 
• 187386-90-9 C₁₂H₁₄ClNO₂ 

Downstream Products

• 53342-53-3 4,6-dichloro-2-methylquinoline 
• 74767-32-1 4-{[1-(4-Hydroxy-phenyl)-meth-(E)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 74767-21-8 4-{[1-(4-Chloro-phenyl)-meth-(E)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 74767-11-6 2-{[1-(4-Hydroxy-phenyl)-meth-(Z)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 74767-08-1 2-{[1-(4-Chloro-phenyl)-meth-(Z)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 74767-19-4 2-{[1-(4-Dimethylamino-phenyl)-meth-(Z)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 74767-16-1 2-{[1-(4-Acetylamino-phenyl)-meth-(Z)-ylidene]-amino}-benzoic acid 6-chloro-2-methyl-quinolin-4-yl ester 
• 503552-63-4 4,6-dichloro-3-formyl-2-(2-hydroxy-ethen-1-yl)quinoline 
• 1392200-85-9 N¹-(6-chloro-2-methylquinolin-4-yl)-N²,N²-dimethylethane-1,2-diamine 
• 1392200-86-0 C₁₅H₂₀ClN₃ 
• 1392200-87-1 6-chloro-2-methyl-N-(3-morpholinopropyl)quinolin-4-amine 
• 1393442-03-9 (E)-N₁-(6-chloro-2-(4-(methylsulfonyl)styryl)quinolin-4-yl)-N₂,N₂-dimethylethane-1,2-diamine 
• 1393442-04-0 (E)-N¹-(6-chloro-2-(2-(pyridin-4-yl)vinyl)quinolin-4-yl)-N²,N²-dimethylethane-1,2-diamine 
• 1393442-05-1 (E)-N₁-(6-chloro-2-(2-(pyridin-4-yl)vinyl)quinolin-4-yl)-N₃,N₃-dimethylpropane-1,3-diamine 

Relevant academic research and scientific papers

Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions

To identity fast-acting, multistage antimalarial agents, a series of pyridylvinylquinoline-triazole analogues have been synthesized via CuAAC. Most of the compounds display significant inhibitory effect on the drug-resistant malarial Dd2 strain at low submicromolar concentrations. Among the tested analogues, compound 60 is the most potent molecule with an EC50 value of 0.04 ± 0.01 μM. Our current study indicates that compound 60 is a fast-acting antimalarial compound and it demonstrates stage specific action at the trophozoite phase in the P. falciparum asexual life cycle. In addition, compound 60 is active against both early and late stage P. falciparum gametocytes. From a mechanistic perspective, compound 60 shows good activity as an inhibitor of β-hematin formation. Collectively, our findings suggest that fast-acting agent 60 targets dual life stages of the malarial parasites and warrant further investigation of pyridylvinylquinoline hybrids as new antimalarials.

Anticancer, antimicrobial activities of quinoline based hydrazone analogues: Synthesis, characterization and molecular docking

Based on the biologically active heterocycle quinoline, a series (18a-p) of quinoline hydrazone analogues were prepared, starting from 6-bromo/6-chloro-2-methyl-quinolin-4-yl-hydrazines. For all the newly synthesized compounds cytotoxic activities were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cancer cell lines. Amongst all the tested compounds, nine compounds (18b, 18d, 18e, 18f, 18g, 18h, 18i, 18j, 18l) exhibited important anti-proliferative activity at 10 μM concentration and were further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM) with GI50 values ranging from 0.33 to 4.87 μM and LC50 values ranging from 4.67 μM to >100j μM. Further, the mean values of GI50, TGI and LC50 of the most potent compound 18j were compared with the clinically used anticancer agents bendamustine and chlorambucil, revealed that the quinolyl hydrazones holds promise as a potential anticancer agents. Further all the newly prepared compounds were screened for their antimicrobial activity. All the quinolyl hydrazones displayed good to excellent antimicrobial activity with MIC values ranging from 6.25 to 100 μg/mL against the tested pathogenic strains. Molecular docking of the synthesized compounds into the active binding site of human DNA topoisomerase I (htopoI) was carried out to predict the binding mode to the DNA topoisomerase I inhibitors. Hopefully in future, compounds based on quinoline core could be used as a lead compounds for designing new anticancer agents.

Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines

There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a Plasmodium falciparum CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound 24 also demonstrates transmission blocking potential. Additionally, the monophosphate salt of 24 exhibits excellent in vivo antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.

Synthesis and identification of quinoline derivatives as topoisomerase I inhibitors with potent antipsoriasis activity in an animal model

Psoriasis is a chronic inflammatory and immune-mediated skin disease. Although certain agents have shown clinical success in treating psoriasis, development of safe and effective strategies for the treatment of this condition remains important. Research suggests that DNA topoisomerase I (Topo I)inhibitors may have potent psoriasis-ameliorating effects. Here, 25 quinoline derivatives were synthesized and identified as Topo I inhibitors. These compounds inhibited the 12–O–tetradecanoylphorbol-13-acetate-induced mouse ear inflammation. The most potent analogs, 5i and 5l, suppressed the expression of inflammatory cytokines in lipopolysaccharide-stimulated HaCaT cells. Additionally, the lead compounds significantly improved imiquimod-induced psoriasis-like inflammation in mice. Moreover, the expression levels of cytokines and inflammatory mediators, such as interleukin (IL)-17A, IL-22, IL-23, nuclear factor-κB subunit p65, tumor necrosis factor-α, and interferon-γ, were dramatically inhibited in the dorsal skin of 5i- and 5l-treated mice. These findings indicate that the inhibition of Topo I activity may potentially be an effective strategy for psoriasis treatment.

Design, synthesis and anti-HIV-1 activity of modified styrylquinolines

Background: Drug resistance and reservoirs of latent viral infection have prevented total eradication of the HIV-virus which underlines the need for continuous efforts in the discovery of new anti-HIV agents. The present study deals with the synthesis of novel compounds based on naturally occurring scaffolds and their evaluation as potential anti-HIV agents. Objective: Design and synthesis of styrylquinoline scaffold based new molecules and evaluation of their anti-HIV-1 activity. Methods: A series of forty three new styrylquinolines (SQLs) was designed and synthesized. The newly synthesized compounds were tested for anti-HIV-1 activity against HIV-1VB59 and HIV-1UG070 primary isolates in TZM-bl cell lines. Results: The most active compounds 9 and 34 (IC50 = 0.5-4.0 μM), also exhibited significant inhibition activity against HIV-1VB51 primary isolate in PBMCs (IC50 = 7.3 μM). Compounds 9 and 34 were also found to inhibit HIV-1 entry into host cells and fusion inhibitory activities. The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents. Conclusion: The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents.

New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis

2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range. Furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they showed intracellular activities similar to those of isoniazid and rifampin in a macrophage model of Mtb infection. Use of the checkerboard method to investigate the association profiles of lead compounds with first- and second-line antituberculosis drugs showed that 2-(quinolin-4-yloxy)acetamides have a synergistic effect with rifampin. Ultimately, the good permeability, moderate rates of metabolism and low risk of drug-drug interactions displayed by some of the synthesized compounds indicate that 2-(quinolin-4-yloxy)acetamides may yield candidates to use in the development of novel alternative therapeutics for tuberculosis treatment.

Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2-Quinolin-4-yloxyacetamides

In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.

SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc 1 inhibitors

A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library. These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex.

Design, synthesis, ADME characterization and antileishmanial evaluation of novel substituted quinoline analogs

In vitro ADME characterization of the lead compound 1 identified for visceral leishmaniasis was undertaken and further structural analogs were synthesized for antileishmanial screening. Compound 1 was highly permeable in intestinal PAMPA model (31 × 10-6 cm/s) and was moderately bound to mouse and human plasma proteins (% bound 85-95%), its blood to plasma concentration ratio was less than 1, but the compound was unstable in blood. Compound 1 was found to have no CYP450 liability with CYP2C9, 2C19, 2D6 and 3A4. It showed inhibition with CYP1A2 with an IC50 value of 0.50 μM. Analogs of 1 were synthesized and subsequently characterized for in vitro activity against the intracellular form of Leishmania donovani. Resulting quinolines were found to have similar efficacy as 1 against the parasite. Compounds 8b and 8f were found to be the most active with IC50 values of 0.84 μM and 0.17 μM, respectively compared to 0.22 μM for compound 1. Of all the analogs tested, 8d was stable in hamster, mouse and human liver microsomes but lost the efficacy with an IC50 of 6.42 μM. Based on the in vitro efficacy and DMPK profile, compounds 8b and 8f seem the best candidates to be screened in further assays.

Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents

An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC50 value of 0.2 μM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.