Trifluoromethyl Moiety Research Articles

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques.

Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca. 0.5 h, whereas for HTB it is ca. 35 h. From a pharmacological point of view, it is interesting to note that HTB is itself highly active as a platelet anti-aggregant agent. Indeed, studies on the clinical profile of both drug and metabolite have shown no significant differences between them. It has been evidenced that HTB displays ability to induce photoallergy in humans. This phenomenon involves a cell-mediated immune response, which is initiated by covalent binding of a light-activated photosensitizer (or a species derived therefrom) to a protein. In this context, small proteins like ubiquitin could be appropriate models for investigating covalent binding by means of MS/MS and peptide fingerprint analysis. In previous work, it was shown that HTB forms covalent photoadducts with isolated lysine. Interestingly, ubiquitin contains seven lysine residues that could be modified by a similar reaction. With this background, the aim of the present work is to explore adduct formation between the triflusal metabolite and ubiquitin as model protein upon sunlight irradiation, combining proteomic and photophysical (fluorescence and laser flash photolysis) techniques. Photophysical and proteomic analysis demonstrates monoadduct formation as the major outcome of the reaction. Interestingly, addition can take place at any of the ε-amino groups of the lysine residues of the protein and involves replacement of the trifluoromethyl moiety with a new amide function. This process can in principle occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.

Synthesis and gas transport properties of new polynorbornene dicarboximides bearing trifluoromethyl isomer moieties

This work reports on the synthesis and ring-opening metathesis polymerization (ROMP) of new structural isomers based on norbornene dicarboximides bearing trifluoromethyl moieties, specifically, N-2-trifluoromethylphenyl- exo- endo-norbornene-5,6-dicarboximide (2a) and N-3-trifluoromethylphenyl- exo- endo-norbornene-5,6-dicarboximide (2b) using tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene] ruthenium dichloride (I), bis(tricyclohexylphosphine) benzylidene ruthenium (IV) dichloride (II), and bis(tricyclohexylphosphine) p-fluorophenylvinylidene ruthenium (II) dichloride (III). It is observed that the –CF3 moiety attached to the ortho position of the aromatic ring increases the thermal and mechanical properties of the polymer, whereas the meta substitution has the opposite effect. A comparative study of gas transport in membranes based on these fluorinated polynorbornenes showed that the –CF3 ortho substitution increases the permeability of the polymer membrane as a consequence of the increase of both the gas solubility and the gas diffusion. In contrast, the gas permeability coefficients of the meta-substituted polymer membrane are rather similar to those of the non-fluorinated one attributed to a lower fractional free volume. The meta-substituted polymer membrane besides showing the largest permselectivity coefficients of all the isomers studied here was also found to have one of the largest permselectivity coefficients reported to date for separating hydrogen/propylene in glassy polynorbornene dicarboximides.

Synthesis, structural characterization, thermal analysis, and DFT calculation of a novel zinc (II)-trifluoro-β-diketonate 3D supramolecular nano organic-inorganic compound with 1,3,5-triazine derivative

A sonochemical method was used to synthesize a novel nano-structure of a zinc(II) organic-inorganic compound [Zn(dapt)2(ttfa)2] (1) [dapt = 2,4-diamino-6-phenyl-1,3,5-triazine and ttfa = 2-thenoyltrifluoroacetonate]. The new nanostructure was characterized by scanning electron microscopy, X-ray powder diffraction, elemental analysis, and thermal analysis. The single-crystal X-ray structure shows that 1 is a discrete coordination compound. Strong intra- and intermolecular hydrogen bonds are observed in the structure with the latter forming chains of molecules running parallel to (110). The chains are further extended into a three-dimensional supramolecular structure by intermolecular CF⋯π interactions between trifluoromethyl and triazine moieties. The coordination number of the zinc(II) ion is six (ZnN2O4), and the coordination sphere is tetragonally elongated octahedral. The structure of the title complex was optimized by DFT calculations.

Design, synthesis and computational evaluation of a novel intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl) benzamide as potential potassium channel blocker in epileptic paroxysmal seizures

The narrow therapeutic range and limited pharmacokinetics of available Antiepileptic drugs (AEDs) have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule targeting voltage gated potassium channels anticipated to have superior pharmacological than existing potassium channel blockers. The compound was synthesized by reacting (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4] benzodiazepine5,11(10H,11aH)-dione with 4-(Trifluoromethyl) benzoic acid (C8H5F3O2) in DMF and N,N′-dicyclohexylcarbodiimide (DCC) which lead to the formation of an intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl)benzamide with a perfect crystalline structure. The structure of the compound was characterized by FTIR, 1H NMR and 13C NMR analysis. The crystal structure is confirmed by single crystal X-ray diffraction analysis. The Structure-Activity Relationship (SAR) studies revealed that substituent of fluoro or trifluoromethyl moiety into the compound had a great effect on the biological activity in comparison to clinically used drugs. Employing computational approaches the compound was further tested for its affinity against potassium protein structure by molecular docking in addition, bioactivity and ADMET properties were predicted through computer aided programs.

Microwave assisted regioselective synthesis and 2D-NMR studies of novel azoles and azoloazines utilizing fluorine-containing building blocks

An efficient regioselective synthesis of novel azoles containing a trifluoromethyl moiety via the 1,3-dipolar cycloaddition reaction under microwave irradiation, using fluorine-containing building blocks methodology was achieved. Furthermore, these novel azoles scaffolds have been employed as the starting material in the synthesis of new azoloazines containing a trifluoromethyl group. An unambiguous structural assignment of the obtained regioisomers was determined using the 2D HMBC NMR techniques as a valuable tool.

ChemInform Abstract: A Facile One‐Pot Synthesis of Novel 1,2,4‐Triazolo[4,3‐a]pyridine Derivatives Containing the Trifluoromethyl Moiety Using Microwave Irradiation.

AbstractThe title compounds exhibit weak antifungal activity.

Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.

Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.

ChemInform Abstract: Synthesis of Pyrazoles Containing Benzofuran and Trifluoromethyl Moieties as Possible Antiinflammatory and Analgesic Agents.

AbstractSome of the synthesized compounds exhibit good antiinflammatory and/or significant analgesic activities.

A Facile One-Pot Synthesis of Novel 1,2,4-Triazolo[4,3-a]Pyridine Derivatives Containing the Trifluoromethyl Moiety Using Microwave Irradiation

A series of novel substituted 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridines are synthesised from 2,3-dichloro-5-(trifluoromethyl)pyridine, hydrazine hydrate as starting materials by multi-step reactions under microwave irradiation. Their chemical structures can be characterised by 1H NMR, MS and elemental analysis. The title compounds exhibit weak antifungal activity.

Selective Solvent-Assisted Linker Exchange (SALE) in a Series of Zeolitic Imidazolate Frameworks.

Solvent-assisted linker exchange (SALE) has recently emerged as an attractive strategy for the synthesis of metal-organic frameworks (MOFs) that are unobtainable via traditional synthetic pathways. Herein we present the first example of selective SALE in which only the benzimiadazolate-containing linkers in a series of mixed-linker zeolitic imidazolate frameworks (ZIF-69, -78, and -76) are replaced. The resultant materials (SALEM-10, SALEM-10b, and SALEM-11, respectively) are isostructural to the parent framework and in each case contain trifluoromethyl moieties. We therefore evaluated each of these materials for their hydrophobicity in condensed and gas phases. We expect that selective SALE will significantly facilitate the design of improved, and potentially complex, MOF materials with new and unusual properties.

Synthesis of pyrazoles containing benzofuran and trifluoromethyl moieties as possible anti-inflammatory and analgesic agents

Abstract Searching for new anti-inflammatory and analgesic agents, we have prepared a series of novel pyrazoles containing benzofuran and trifluoromethyl moieties. The pyrazole derivatives have been synthesized via two routes starting from 5-(3-(trifluoromethyl)phenyl azo) salicylaldehyde. The first route involved the synthesis of 2-acetylbenzofuran and then treatment with aldehydes to afford the corresponding chalcones. The cyclization of the latter chalcones with hydrazine hydrate led to the formation of new pyrazoline derivatives. The second route involved the synthesis of benzofuran-2-carbohydrazide and then treatment with formylpyrazoles, chalcones and ketene dithioacetal derivatives to afford the corresponding pyrazole derivatives. Some of the synthesized compounds exhibited anti-inflammatory and analgesic activities.

ChemInform Abstract: Advances in Catalytic Enantioselective Fluorination, Mono‐, Di‐, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

AbstractReview: 211 refs.

Opposing orientations of the anti-psychotic drug trifluoperazine selected by alternate conformations of M144 in calmodulin.

The anti-psychotic drug trifluoperazine (TFP) is an antagonist observed to bind to calcium-saturated calmodulin ((Ca(2+) )4 -CaM) at ratios of 1:1 (1CTR), 2:1 (1A29), and 4:1 (1LIN). Each structure contains one TFP bound in the hydrophobic cleft of the C-domain of CaM. However, the orientation of the trifluoromethyl (CF3 ) moiety differs among them: it is buried in the C-domain cleft of 1A29 and 1LIN, but protrudes from 1CTR. We report a 2.0 Å resolution crystallographic structure (4RJD) of TFP bound to the (Ca(2+) )-saturated C-domain of CaM (CaMC ). The asymmetric unit contains two molecules of (Ca(2+) )2 -CaMC . Chain backbones were nearly identical, but the orientation of TFP in the cleft of Chain A matched 1A29/1LIN, while TFP bound to Chain B matched 1CTR. This was accommodated by a flip of the M144 sidechain and small changes in sidechains of M109 and M145. Docking simulations suggested that the rotamer conformation of M144 determined the orientation of TFP within the cleft of (Ca(2+) )2 -CaMC . Chains A and B show that the open cleft of (Ca(2+) )2 -CaMC is promiscuous in accepting TFP in reversed directions under the same crystallization conditions. Observing multiple orientations of an antagonist bound to a single protein highlights the challenge of designing highly specific pharmaceuticals, and may have importance for QSAR of other CF3 -containing drugs such as fluoxetine (anti-depressant) or efavirenz (reverse transcriptase inhibitor). This study emphasizes that a single structure of a complex represents an energetically accessible state, but does not necessarily show the full range of energetically equivalent states.

Synthesis and antimycobacterial properties of ring-substituted 6-hydroxynaphthalene-2-carboxanilides

In this study, a series of twenty-two ring-substituted 6-hydroxynaphthalene-2-carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, Mycobacterium avium complex and M. avium subsp. paratuberculosis. Derivatives substituted by trifluoromethyl, bromo, methyl and methoxy moieties in C′(3) and C′(4) positions of the anilide ring showed 2-fold higher activity against M. tuberculosis than isoniazid and 4.5-fold higher activity against M. avium subsp. paratuberculosis than rifampicin. 6-Hydroxy-N-(2-methylphenyl)naphthalene-2-carboxamide had MIC=29μM against M. avium complex. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using the THP-1 cells, and no significant lethal effect was observed. The structure–activity relationships are discussed.

Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions.

Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science.1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere.2 For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine.3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis.3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.”4 The field has undoubtedly undergone great change within the last two decades. As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure ​(Figure11). Figure 1 Molecules of medicinal interest bearing C–F and C–CF3 stereocenters.

Trifluoromethyl-derived enaminones and their difluoroboron complexes: Synthesis, crystal structure and electrochemistry properties

Abstract Twelve trifluoromethylated enaminones including seven N,O-bidentate, three N,O,O- and one N,N,O-tridentate, and one N,N,O,O-tetradentate ligands that can include multiple coordination centers as well as redox-active and photosensitive units have been prepared. Seven new difluoroboron complexes 23–29 were prepared by the reaction of BF3·OEt2 in acetonitrile in the presence of Et3N with five bidentate ligands, one tridentate ligand and one tetradentate ligand. Their crystal structure, UV–vis absorption and redox properties have been studied. The role of the trifluoromethyl and difluoroboron moieties and their ability to form F H intra- and inter-complexes bonds leading to multidimensional networks have been also featured.

Metal-Free Photocatalytic Radical Trifluoromethylation Utilizing Methylene Blue and Visible Light Irradiation

The use of organofluorine compounds, especially those with an incorporated trifluoromethyl moiety, has increased dramatically in both the pharmaceutical and agrochemical industry. It has therefore become imperative to develop a mild and efficient synthetic technique for the inclusion of trifluoromethyl groups. Herein, we report the first use of methylene blue as a photosensitizer for the catalytic radical trifluoro- and hydrotrifluoromethylation of electron-rich heterocycles as well as terminal alkenes and alkynes under visible light irradiation. These reactions proceed with moderate to good yields at low catalyst concentrations; short irradiation times; and most importantly, without the need for potentially toxic transition-metal catalysts. In this work, considerable emphasis was also placed on understanding the kinetics of the mechanistically key steps through the use of laser flash photolysis techniques to more efficiently optimize the reaction conditions.

Design, Synthesis, Structure‐Activity Relationship and Insecticidal Activities of Trifluoromethyl‐Containing Sulfiliminyl and Sulfoximinyl Phthalic Acid Diamide Structure

AbstractDue to a novel mode action, low toxicity to mammals and low residue characteristics, phthalic acid diamides have aroused considerable interests in agricultural chemistry. With introduction of N‐cyano, N‐trifluoroacetyl, N‐carbamoylsulfiliminyl and sulfoximinyl substituents into phthalamides, 12 novel derivatives containing trifluoromethyl moiety were designed and synthesized. All title compounds were characterized by 1H NMR and high‐resolution mass spectrometry. The preliminary results of biological activity assessment indicated that some title compounds exhibited moderate to good insecticidal activities against oriental armyworm (Pseudaletia separata Walker). In particular, Va gave higher activity against oriental armyworm and diamondback moth. The present work reported that the new trifluoromethylated diamides incorporating N‐trifluoroacetylsulfoximinyl moieties are potential lead compounds for further structure optimization, providing some insight into the relating structure‐activity relationship.

Discovery of 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating hypertension

We identified 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating hypertension. Docking studies using human and murine sEH X-ray crystal structures revealed steric hindrance around the side chain of Phe406 of murine sEH. The trifluoromethyl moiety (11) was replaced with a trifluoromethoxy moiety (12) to prevent steric clash, and improved murine sEH inhibitory activity was observed. The oral administration of 12, 20, and 37 at a dose of 30mg/kg reduced blood pressure in spontaneously hypertensive rat, but had little effect on blood pressure in normotensive rat.

New pyridazine–fluorine derivatives: Synthesis, chemistry and biological activity. Part II

A comprehensive study concerning synthesis, structure and biological activity of new pyridazine–fluorine (PYF) derivatives is presented. The first synthesis of PYF derivatives in phase-transfer catalysis (PTC) under microwave (MW) and conventional thermal heating (TH) is reported. Under MW irradiation the consumed energy decreases considerably, the amount of used solvent in liquid phase is at least five-fold less comparative with conventional TH, while PTC did not use solvents. Consequently these reactions could be considered environmentally friendly. Also, the reaction time decrease substantially and, in some cases, the yields are higher. A feasible explanation for MW efficiency is presented. Regiochemistry and chorochemistry involved in these reactions are also discussed; the reactions are regioselective and chorospecific or choroselective, respectively. Ten new pyridazine–fluorine cycloadducts are obtained. The in vitro antibacterial and antifungal activities of the PYF compounds were tested. Introduction of a trifluoromethyl moiety on the pyridazine skeleton is leading to an increasing of the antimicrobial activity. Structure–activity correlationships have been done.