71173-28-9

Upstream product

• 108-31-6 maleic anhydride 
• 328-74-5 3,5-Bis-(trifluoromethyl)aniline 
• 72291-55-5 (Z)-4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxobut-2-enoic acid 

Downstream Products

• 1377806-96-6 C₂₅H₁₉F₆NO₃ 
• 1377807-01-6 C₂₉H₂₁F₆NO₃ 
• 1377806-97-7 C₂₅H₁₈ClF₆NO₃ 
• 1377806-99-9 C₂₆H₂₁F₆NO₃ 
• 1264932-15-1 ethyl 10-(3,5-bis(trifluoromethyl)phenyl)-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate 

Relevant academic research and scientific papers

Comparative reactivity analysis of small-molecule thiol surrogates

Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since covalent and non-covalent interactions are both contributing to the affinity of these compounds, evaluation of their reactivity is a key-step to find feasible warheads. There are well-established HPLC- and NMR-based kinetic assays to tackle this task, however, they use a variety of cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine and GSH. The diverse nature of the thiol sources often makes the results incomparable that prevents compiling a comprehensive knowledge base for the design of covalent inhibitors. To evaluate kinetic measurements from different sources we performed a comparative analysis of the different thiol surrogates against a designed set of electrophilic fragments equipped with a range of warheads. Our study included seven different thiol models and 13 warheads resulting in a reactivity matrix analysed thoroughly. We found that the reactivity profile might be significantly different for various thiol models. Comparing the different warheads, we concluded that – in addition to its human relevance - glutathione (GSH) provided the best estimate of reactivity with highest number of true positives identified.

Photochemical Reaction of N,N-Dimethylanilines with N-Substituted Maleimides Utilizing Benzaldehyde as the Photoinitiator

Photoorganocatalysis constitutes a powerful domain of photochemistry and organic synthesis. The scaffold of pyrrolo[3,4-c]quinolinoles exhibits interesting and potent inhibition against various enzymes, making them really promising pharmaceutical targets. Herein, we describe a photochemical methodology for the reaction of N,N-dimethylanilines with N-substituted maleimides, utilizing benzaldehyde as the photoinitiator. A variety of substituted N,N-dimethylanilines and N-substituted maleimides were converted into the corresponding adducts in moderate to high yields.

Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments

Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Herein, we present a toolbox of fragments containing a 3,5-bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity, aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine-containing enzymes.

An electrophilic warhead library for mapping the reactivity and accessibility of tractable cysteines in protein kinases

Targeted covalent inhibitors represent a viable strategy to block protein kinases involved in different disease pathologies. Although a number of computational protocols have been published for identifying druggable cysteines, experimental approaches are limited for mapping the reactivity and accessibility of these residues. Here, we present a ligand based approach using a toolbox of fragment-sized molecules with identical scaffold but equipped with diverse covalent warheads. Our library represents a unique opportunity for the efficient integration of warhead-optimization and target-validation into the covalent drug development process. Screening this probe kit against multiple kinases could experimentally characterize the accessibility and reactivity of the targeted cysteines and helped to identify suitable warheads for designed covalent inhibitors. The usefulness of this approach has been confirmed retrospectively on Janus kinase 3 (JAK3). Furthermore, representing a prospective validation, we identified Maternal embryonic leucine zipper kinase (MELK), as a tractable covalent target. Covalently labelling and biochemical inhibition of MELK would suggest an alternative covalent strategy for MELK inhibitor programs.

Catalyst and Additive-Free Diastereoselective 1,3-Dipolar Cycloaddition of Quinolinium Imides with Olefins, Maleimides, and Benzynes: Direct Access to Fused N,N′-Heterocycles with Promising Activity against a Drug-Resistant Malaria Parasite

A convenient and eco-friendly synthesis of various fused N-heterocyclic compounds through catalyst and additive-free 1,3 dipolar cycloadditions of quinolinium imides with olefins, maleimides, and benzynes in excellent yields and diastereoselectivities is reported. The thermally controlled diastereoselective [3 + 2] cycloaddition reaction between quinolinium imides and olefins provided cis-isomers at low temperature and trans-isomers at high temperature. A reaction between quinolinium imides with substituted maleimides gave four-ring-fused N-heterocyclic compounds in high yields as a single diastereomer. The aryne precursors also provided four-ring-fused N,N′-heterocyclic compounds in high yields. The in vitro antiplasmodial activity of selected molecules revealed that this class of molecules possesses potential for ongoing studies against malaria.

Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans

A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6′-chloro-5-(4-fluorophenyl)-7′-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3′-1H-indole]-2′,4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy. Synergy from stereochemical complexity: An attempt to synthesize analogues of a known spiroindolinone led to a series of diastereomers. One spiroindolinone, termed synazo-1, was shown to exhibit potent activity (300 pM) against C. albicans in the presence of fluconazole. Synazo-1 is a true synergizer and was also highly active against some drug-resistant C. albicans strains.

Multinuclear NMR studies and Ab initio structure calculations of hindered phencyclone Diels-Alder adducts from symmetrical cyclic dienophiles: Cyclohexene, vinylene carbonate, vinylene trithiocarbonate and two N-aryl maleimides

A series of hindered Diels-Alder adducts have been prepared from phencyclone, 1, with various unusual symmetrical cyclic dienophiles, including cyclohexene, 2a; vinylene carbonate, 2b; vinylene trithiocarbonate, 2c; and the N-aryl maleimides: N-(4-dimethy