370-35-4

Usage

Uses

Used in Pharmaceutical Industry:
Diethyl [(alpha,alpha,alpha-trifluoro-m-toluidino)methylene]malonate is used as a building block in the synthesis of various organic compounds, particularly in the pharmaceutical industry. Its unique structure and properties make it a valuable component in the development of new drugs and medicinal compounds.
Used in Organic Synthesis:
In the field of organic synthesis, diethyl [(alpha,alpha,alpha-trifluoro-m-toluidino)methylene]malonate is employed as a reagent for the preparation of a wide range of organic compounds. Its versatility and reactivity contribute to the synthesis of various chemical entities, including pharmaceuticals, agrochemicals, and other specialty chemicals.
Used in Research and Development:
diethyl [(alpha,alpha,alpha-trifluoro-m-toluidino)methylene]malonate is also utilized in research and development settings, where it serves as a key intermediate in the synthesis of novel organic molecules. Its unique properties and reactivity make it an essential tool for chemists working on the design and synthesis of new chemical entities with potential applications in various industries.

Upstream product

• 98-16-8 3-trifluoromethylaniline 
• 105-53-3 diethyl malonate 
• 87-13-8 diethyl 2-ethoxymethylenemalonate 

Downstream Products

• 391-02-6 4-hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 
• 391-02-6 ethyl 4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 
• 1159590-65-4 ethyl 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 
• 1092179-47-9 1-ethyl-N-(4-methoxybenzyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide 
• 1365252-50-1 C₁₉H₁₃ClF₄N₂O₂ 
• 1373767-12-4 ethyl 2-(3-methoxyphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 
• 1373767-13-5 ethyl 4-oxo-2-(3-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 
• 1373767-14-6 ethyl 2-(3-chlorophenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 
• 1370478-26-4 (2S)-2-({[4-hydroxy-7-(trifluoromethyl)-3-quinolyl]carbonyl}amino)-3-phenylpropanoic acid 
• 1370478-28-6 (2R)-2-({[4-hydroxy-7-(trifluoromethyl)-3-quinolyl]carbonyl}amino)-3-phenylpropanoic acid 
• 1370478-34-4 ethyl (2S)-2-({[1-ethyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-3-quinolinyl]carbonyl}amino)-3-phenylpropanoate 
• 1370478-36-6 ethyl (2R)-2-({[1-ethyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-3-quinolinyl]carbonyl}amino)-3-phenylpropanoate 
• 1370478-42-4 (2S)-2-({[1-ethyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-3-quinolinyl]carbonyl}amino)-3-phenylpropanoic acid 
• 1370478-44-6 (2R)-2-({[1-ethyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro-3-quinolinyl]carbonyl}amino)-3-phenylpropanoic acid 

Relevant academic research and scientific papers

Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay

Type-1 ryanodine receptor (RyR1) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca2+ from the SR. Genetic mutations of RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 causes leakage of Ca2+ from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca2+ in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyR1 channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyR1 channel inhibitors.

Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators

Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.

Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies

In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.

Synthesis, characterization and antimicrobial studies of some new trifluoromethyl quinoline-3-carbohydrazide and 1,3,4-oxadiazoles

The present paper describes the synthesis of two new series of 7-(trifluoromethyl)-4-hydroxy substituted quinoline carbohydrazide derivatives (6a-e and 7a-g) and N-alkyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-7- (trifluoromethyl) quinolin-4-amine derivatives (9a-f). Newly synthesized compounds were characterized by spectral studies. The structure of 9a was evidenced by X-ray crystallographic study. Synthesized compounds were screened for their antibacterial performance against Mycobacterium smegmatis and Pseudomonas aeruginosa. Antifungal activity was also carried out on the fungal stains Candida albicans and Penicillium chrysogenum. Compounds 7a and 9c showed significant antimicrobial activity against all the tested microorganisms. Among all the compounds, 6d and 6e showed the lowest MIC value of 6.25 μg mL -1 against Mycobacterium smegmatis indicating these compounds can be possible future antituberculosis agents. 2014 the Partner Organisations.

Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA

A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities.

Design and regioselective synthesis of trifluoromethylquinolone derivatives as potent antimicrobial agents

Three series of new trifluoromethyl substituted quinolone derivatives were synthesized (4a-f, 6a-f and 8a-f) from corresponding substituted anilines by multi-step reactions. The regioselective alkylation with different alkyl halides were carried out by approaching two different routes to get the final products in good yield. Newly synthesized compounds were characterized by spectral study and also by C, H, N analyses. Three dimensional structure of 2b and 4b were also confirmed by single crystal X-ray studies. The final compounds (4a-f, 6a-f and 8a-f) were screened for their in-vitro antibacterial and antifungal activity by well plate method (zone of inhibition). The results revealed that, compounds 4a, 6b, 6c and 8e showed significant antibacterial activity as compared to the standard drug Ciprofloxacin. The compound 8a was found to be a potent antifungal agent.

Synthesis of novel optically pure α-amino acid functionalised-7- trifluoromethyl substituted quinolone derivatives and their antibacterial activity

7-Trifluoromethyl-4-hydroxy quinoline-3-carboxylic acid ethyl ester was prepared from 3-amino benzotrifluoride and EMME. The hydroxyquinoline was reacted with amino acids to furnish amino acid funtionalised quinolines (5, 6, 7). The compounds were alkylated by ethyl iodide followed by hydrolysis afforded the title compounds in good yields. They were screened for their antibacterial activity for in vitro against Gram +ve and Gram -ve bacterial strains and found 11e and 11b as promising compounds.

Synthesis and structure-activity relationships of new quinolone-type molecules against trypanosoma brucei

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei, Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC50 = 47 nM) and T. b. rhodesiense (IC50 = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.

Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials

Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

A small-molecule inhibitor of nipah virus envelope protein-mediated membrane fusion

Nipah virus (NiV), a highly pathogenic paramyxovirus, causes respiratory disease in pigs and severe febrile encephalitis in humans with high mortality rates. On the basis of the structural similarity of viral fusion (F) proteins within the family Paramyxoviridae, we designed and tested 18 quinolone derivatives in a NiV and measles virus (MV) envelope protein-based fusion assay beside evaluation of cytotoxicity. We found five compounds successfully inhibiting NiV envelope protein-induced cell fusion. The most active molecules (19 and 20), which also inhibit the syncytium formation induced by infectious NiV and show a low cytotoxicity in Vero cells, represent a promising lead quinolone-type compound structure. Molecular modeling indicated that compound 19 fits well into a particular protein cavity present on the NiV F protein that is important for the fusion process. 2009 American Chemical Society.