Search Results (117)

Fluoroalkyl-substituted organoboron compounds are valuable building blocks for organic synthesis and for the development of functional molecules in medicinal chemistry, agrochemicals, and materials science. Building on our previous work on difluoromethyl-substituted borates, we report the synthesis and structural characterization of trifluoromethylated borates, 2-aryl-4,4,5,5-tetramethyl-2-(trifluoromethyl)-1,3,2-dioxaborolan-2-uide salts ([pinB(Aryl)CF₃]⁻). Treatment of pinB–Aryl boronates (pinB = 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) with trimethyl(trifluoromethyl)silane (Ruppert–Prakash reagent) in the presence of potassium tert-butoxide and 18-crown-6 ether (18-C-6) afforded the corresponding trifluoromethylated borates as isolable crystalline compounds. Compared with the related difluoromethylated borates, the CF₃ substituent increases the tendency of [pinB(Aryl)CF₃]⁻ to exhibit hygroscopic behavior, as supported by a hydrated crystal structure and the formation of a hygroscopic product. The isolable trifluoromethylborates can serve as reservoirs of electrophilic trifluoromethyl radicals upon oxidation. Full article

Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC₅₀ of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC₅₀ values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties. Full article

This study presents unique polymeric materials applicable to plastic substrates for use in flexible-display devices that overcome the trade-off between low linear coefficients of thermal expansion (CTE) and low thickness-direction birefringence (Δn_th) while combining a very high T_g, sufficiently high thermal stability, excellent optical transparency, good solubility, and minimum-required ductility. Polyimide (PI) films obtained from 1,2,3,4-cyclobutanetetracarboxylic dianhydride (CBDA) with 2,2′-bis(trifluoromethyl)benzidine (TFMB) under different conditions resulted in widely varying CTE values and provided a clear CTE–Δn_th correlation, which can be regarded as a virtual lower boundary in the CTE–Δn_th relationship for various PI systems. The pristine CBDA/TFMB and CpODA/TFMB (CpODA = norbornane-2-spiro-α-cyclopentanone-α′-spiro-2″-norbornane-5,5″,6,6″-tetracarboxylic dianhydride) systems were modified using numerous specifically designed monomers, i.e., a vertical-alignment-type liquid-crystalline diamine and cardo-type and spiro-type monomers. However, it was very challenging to overcome the trade-off between low CTE and low Δn_th, that is, to significantly exceed this lower boundary by modifying the pristine systems, while ensuring other target properties. One of the keys to achieving the present goal was compatibility with chemical imidization or one-pot polymerization processes (i.e., high solubility of the PIs), because these processes were more advantageous in reducing CTE and enhancing film transparency than the conventional two-step process. The modifications using phenyl-substituted xanthene-pendant 2,7-diaminofluorene and fluorene-pendant 2,3,6,7-xanthenetetracarboxylic dianhydride exhibited a prominent effect on overcoming the trade-off without the help of any fillers, while combining other excellent target properties. Polarized FT-IR difference spectra measured at varying incidence angles suggested that these side groups, which are connected perpendicularly to the PI main chains, align in the Z-direction, rationalizing the observed prominent effect. Thus, unique high-temperature transparent materials applicable to plastic substrates were successfully obtained in this study. Full article

Background: Phenothiazine derivatives bearing trifluoromethyl substituents have attracted increasing interest as multifunctional scaffolds in drug repositioning strategies, particularly in cancer and infectious diseases. Structural modification of classical phenothiazines by incorporation of a quinoline moiety has previously been shown to enhance biological activity. Objectives: The present study aimed to develop an efficient synthesis of 8-trifluoromethylquinobenzothiazines and to evaluate the anticancer and antibacterial potential of their N-substituted analogues inspired by triflupromazine, trifluoperazine, and fluphenazine. Methods: 6H-8-Trifluoromethylquinobenzothiazine was synthesized by cyclization of 2-amino-4-trifluoromethylbenzenethiol and 3-bromo-2-chloroquinoline. The resulting quinobenzothiazine, unsubstituted at the nitrogen atom, was subjected to N-alkylation reactions to afford eleven new 6-dialkylaminoalkyl derivatives. Structural elucidation was performed using NMR and HRMS techniques. Anticancer activity was evaluated by MTT assay against human breast (MDA-MB-231), pancreatic (Mia-PaCa-2), and lung (A-549) carcinoma cell lines, as well as normal HaCaT keratinocytes. Antibacterial activity was assessed by MIC/MBC determination against selected Gram-positive and Gram-negative reference strains and clinical isolates. Results: Among the synthesized compounds, derivatives 8 and 12 exhibited the most favorable anticancer profiles, showing micromolar cytotoxicity (IC₅₀ ≈ 4–10 µM) against lung and pancreatic cancer cells combined with moderate selectivity toward cancer cells over normal keratinocytes. Compound 6 displayed lower cytotoxic potency but a notably high selectivity index due to minimal toxicity toward normal cells. In antibacterial assays, compound 3 exhibited activity against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus isolate, with MIC values ranging from 7.8 to 15.6 µg/mL. The corresponding MBC values were equal to or twofold higher than the MICs (MBC/MIC = 1–2), fulfilling commonly accepted criteria for bactericidal activity (MBC/MIC ≤ 4). OD-based growth kinetics confirmed concentration-dependent inhibition of S. aureus growth. Conclusions: The obtained results identify 8-trifluoromethylquinobenzothiazines as a promising class of multifunctional compounds. Selected derivatives combine anticancer activity with acceptable selectivity or display potent antibacterial effects against clinically relevant Gram-positive pathogens. Full article

In the present study the stereoselective addition of malononitrile to trifluoromethyl arylketimines promoted by chiral iminophosphoranes was investigated. A panel of structurally diverse enantiopure bifunctional superbases, which include thiourea or squaramide unit and a basic site connected by a chiral scaffold, was tested in the asymmetric organocatalytic reaction, to afford an adduct featuring a quaternary stereocenter, in up to a 87/13 enantiomeric ratio. The product was then converted in a single step transformation into the corresponding enantioenriched α-CF₃ substituted quaternary aminoester, without any loss of stereochemical integrity. The absolute configuration of the final product was established by chemical correlation of the chiral compound with a known molecule. Preliminary computational studies were performed in order to elucidate the reaction mechanism and rationalize the stereochemical outcome of the reaction. Full article

A strategy for constructing trifluoromethylated spiroisoxazolones has been developed. This approach relies on the 1,3-dipolar cycloaddition of CF₃-substituted nitrile imines, generated in situ from trifluoroacetyl hydrazonoyl bromides and K₂CO₃, with the exocyclic double bond of 4-benzylidene-3-methylisoxazol-5(4H)-ones. The reaction provides a series of trifluoromethylated spiro(isoxazolone-pyrazoline) derivatives in moderate to high yields (up to 93%). The protocol exhibits broad substrate compatibility with respect to aromatic substituents on both reaction partners. To the best of our knowledge, the introduction of a trifluoromethyl group at the 3-position of the pyrazoline ring via nitrile imine cycloaddition chemistry has not been previously reported. The resulting products incorporate a valuable CF₃-substituted pyrazoline pharmacophore spiro-fused to an isoxazolone core and may be of interest for medicinal chemistry programs. Full article

Background: In this study, we report a novel series of proline- and pipecolic acid-based small molecules designed as allosteric inhibitors of the NS2B/NS3 serine proteases from dengue and Zika viruses, key targets in antiviral drug discovery. Results: Enzymatic studies revealed that S-proline derivatives bearing electron-withdrawing substituents on the aromatic ring, particularly that with a trifluoromethyl group in meta position (i.e., compound 3, IC₅₀ = 5.0 µM), were the most potent against DENV NS2B/NS3, while nitro-substituted inhibitors were mostly effective only against the ZIKV protease. R-configured pipecolic acid-based derivatives were the only ones active against DENV NS2B/NS3, even if the mid-micromolar range; however, they demonstrated improved cellular efficacy since inhibitors 24 and 27 exhibiting strong activity in a DENV2 protease reporter gene assay (EC₅₀ = 5.2 and 5.1 µM, respectively). All compounds showed no cytotoxicity (CC₅₀ > 100 µM) and were selective for the viral protease over off-target serine proteases. Structure-based approaches were exploited to map the druggable allosteric site close to Asn152. Conclusions: Our findings led us to identify proline and pipecolic acid-based inhibitors as promising leads for the development of selective flaviviral NS2B/NS3 allosteric inhibitors. Full article

Thiourea and structurally related urea derivatives are widely recognised for their ability to transport anions through hydrogen bonding interactions. The strength of these interactions correlates with the electronegativity of the ligand and the acidity of the NH hydrogens involved. Thiourea, being more acidic than urea, exhibits partial deprotonation in the presence of certain anions such as organic carboxylates, fluoride, and bromide, while remaining resistant to deprotonation by chloride. This behaviour suggests a degree of selectivity toward chloride ions. Additionally, while carbamide-containing molecules tend to aggregate—potentially reducing their ion-binding efficiency—thiourea derivatives show reduced aggregation, preserving their binding capabilities. In this study, we report the synthesis and characterisation of 21 novel thiourea derivatives obtained by reacting 2-aminobenzoylamino acid esters with various substituted phenyl isothiocyanates. Seven similar thiourea-containing molecules were made as a comparison—without the amino acids—by reacting aniline with the different phenyl isothiocyanates. The reaction kinetics were found to be influenced primarily by the electronic nature of the substituents on the phenyl ring. Electron-withdrawing groups (EWGs), such as para-nitro, 3,5-bis(trifluoromethyl), and fluorine, accelerated the reaction, while electron-donating groups (EDGs), such as para-methoxy, slowed it down. Interestingly, the nature of the amino acid precursors had no significant impact on reaction time; however, reactions with aniline proceeded the fastest. Solvent choice also played a role: reactions in N,N-dimethylformamide (DMF) proceeded faster than in acetone, although with reduced yields. Consequently, reaction conditions were optimised to balance time efficiency and product yield. To evaluate the chloride ion-binding properties of the synthesised compounds, ¹H NMR titration experiments were conducted in deuterated dimethyl sulfoxide (DMSO-d₆). The association constants (K_a) derived from these studies revealed a clear correlation with the electronic nature of the substituents. Compounds bearing EWGs exhibited enhanced chloride binding, while those with EDGs showed diminished binding affinity. Surprisingly, the presence of amino acid moieties led to a decrease in K_a values, despite the electron-withdrawing nature of the amide groups. This suggests that steric or conformational factors may play a role in modulating binding strength. Overall, the synthesised thiourea derivatives demonstrate mild, reversible chloride ion-binding behaviour, making them promising candidates for further development as selective anion receptors. The insights gained from this study contribute to a deeper understanding of structure–activity relationships in anion-binding systems and may inform the design of future supramolecular architectures with tailored ion recognition properties. Full article

Two diruthenium(II,II) naphthyridine complexes coordinated with 4-trifluoromethylbenzoate (O₂CPh-4-CF₃) and 3,5-bis(trifluoromethyl)benzoate (O₂CPh-3,5-diCF₃) ligands, formulated as [Ru₂(npc)₂(O₂CPh-4-CF₃)₂] (4; npc = 1,8-naphthyridine-2-carboxylate) and [Ru₂(npc)₂(O₂CPh-3,5-diCF₃)₂] (5), respectively, were synthesized and structurally characterized. Single-crystal X-ray diffraction analysis revealed that both 4 and 5 form a direct metal–metal bond between the two Ru ions (2.2893(8) and 2.2896(7) Å, respectively) and adopt a paddlewheel-type structure in which two npc and two trifluoromethyl-substituted benzoate ligands are coordinated to a Ru₂⁴⁺ core with a cis-2:2 arrangement. The temperature dependence of the magnetic susceptibility measurements of 4 and 5 exhibited very large zero-field splitting (D = 242 and 246 cm⁻¹, respectively) of the triplet ground state of the Ru₂⁴⁺ core, similar to that of [Ru₂(npc)₂(O₂CPh)₂] (3; D = 238 cm⁻¹). Owing to the effects of the trifluoromethyl substituents, compared with 3, 4 and 5 showed (i) a significant blue shift of the absorption bands in the visible region and (ii) a positive shift of the redox potentials, with both shifts becoming more pronounced as the number of trifluoromethyl substituents increased. These experimental results are in good agreement with the electronic structure results obtained from density functional theory calculations. Full article

Heterogeneous catalysts comprising immobilized nickel(II) complexes bearing a fluorine- or trifluoromethyl-substituted iminopyridine ligand (X_n-C₆H_5–n-N=C (CH₃)-C₅H₅N, X = F or CF₃) in fluorotetrasilicic mica interlayers were prepared by reacting Ni²⁺-exchange fluorotetrasilicic mica with the appropriate ligand. Upon activating the precatalyst with triethylaluminum or triisobutylaluminum, the generated active species showed catalytic activity for ethylene oligomerization, yielding low-molecular-weight polyethylene (PE), ethylene oligomers, and wax-like PE. The oligomer distribution almost agreed with what we expected according to the Schultz–Flory distribution. However, the amount of solid products was much higher than the theoretical value, indicating that at least two active species were formed, i.e., the oligomer and low-molecular-weight PE. The precatalyst with a 2,4-F₂C₆H₃ group on the imino nitrogen atom activated by triethylaluminum showed the highest catalytic activity for ethylene oligomerization (408 g-C₂ g-cat⁻¹ h⁻¹), with selectivities to the liquid and solid products of 51.0% and 11.5%, respectively, with the rest of the product corresponding to wax-like PE. Meanwhile, the highest selectivity to the liquid product (66.7% at 233 g-C₂ g-cat⁻¹ h⁻¹) was obtained using the precatalyst with a 2-FPh group on the imino nitrogen atom activated by triisobutylaluminum. Full article

Recently published halogenated anilides of chlorinated and trifluorinated cinnamic acids, such as (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide, or (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide, showed excellent antibacterial activities in vitro against Gram-positive bacteria, especially against reference and quality control strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, as well as against representatives of multidrug-resistant bacteria, clinical isolates of methicillin-resistant S. aureus (MRSA), and vancomycin-resistant E. faecalis (VRE) with minimum inhibitory concentrations (MICs) against staphylococci < 0.2 µg/mL and against enterococci < 4 µg/mL. It should be noted that all these compounds are rather lipophilic (software predicted log P values close to 5) and carry electron-withdrawing substituents that allow them to be classified as so-called Michael acceptors. All these facts inspired further investigation of the spectrum of effectiveness against other bacteria, and the most effective agents with various substitutions in both the anilide part and on the phenyl ring of the parent cinnamic acid were chosen and tested against selected pathogenic Gram-negative bacteria, such as reference and quality control strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27859, and a clinical isolate of Klebsiella pneumoniae 797. Unfortunately, it was found that none of the selected halogenated anilide derivatives with such high potency against Gram-positive bacteria demonstrated better efficacy against the tested Gram-negative bacteria than a MIC of 256 µg/mL. Full article

Background: Theophylline, which is biologically important and found in tea, coffee, and cocoa beans, can be synthesized chemically or by direct extraction and concentration from natural sources. Theophylline derivatives have garnered attention in recent years for their potential therapeutic effects on Mycobacterium tuberculosis, antihistaminic, anti-inflammatory, and anticancer. Also, trifluoromethyl (CF₃) group has also been widely used in drug and agrochemical design. Methods: In this study, a series of new theophylline derivatives containing substituted trifluoromethyl and trifluoromethoxy groups were synthesized. The structures of these new compounds were confirmed by NMR, FT-IR, and elemental analyses. Additionally, the anticancer activities of the molecules were analyzed against VEGFR-2, CYP P450, and estrogen receptor by molecular docking method. Furthermore, in vitro biological effects of the compounds were comprehensively evaluated in cancer (A549 and HeLa) and normal (BEAS-2B) cells. Cell viability was assessed by MTT assay, and selectivity index (SI) values were calculated to determine tumor-specific toxicity. Results: N(7)-substituted theophyllines were prepared by the reaction of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (theophylline) and trifluoromethyl substituted benzyl halide compounds. The synthesized N(7)-substituted theophyllines were obtained as white powder in high yield. The structure of synthesized compounds was confirmed by various spectroscopic techniques such as ¹H, ¹³C, ¹⁹F NMR, and FT-IR spectroscopy, and elemental analysis. The highest interaction was recorded as −5.69 kcal/mol for 3-CF₃ substituted against VEGFR-2 structure while the best binding affinity was determined for 4-OCF₃ substituted with −6.69 kcal/mol against Human Cytochrome P450 with in silico analysis. The in vitro anticancer activities of the molecules were also evaluated against A549 and HeLa cells, and displayed considerably higher cytotoxicity with 2-CF₃, 3-CF_3, and 4-CF₃ substituted molecules in Hela and A549 cell line. To elucidate the molecular mechanism, apoptosis-related gene expression changes were analyzed by RT-qPCR in A549 and HeLa cells treated with compound 2-CF₃. Significant upregulation of pro-apoptotic markers and downregulation of anti-apoptotic genes were observed. Consistently, ELISA-based quantification confirmed increased protein levels of Caspase-3, BAX, and Cytochrome C, and decreased BCL-2, validating the apoptotic mechanism at the protein level. Also, the antibacterial and antibiofilm activity details of the molecules were evaluated against DNA Gyrase, and SarA crystal structures by molecular docking method. The highest interaction was recorded as −5.56 kcal/mol for 2-CF₃ substituted with H-bonds with Asn46, Val71, Asp73, and Thr165 against DNA Gyrase crystal structure while 3-CF₃ substituted has the best binding affinity against SarA. The in vitro antimicrobial effects of the molecules were also evaluated. Conclusions: The synthesized molecules may provide insight into the development of potential therapeutic agents to the increasing antimicrobial resistance and biofilm-forming capacity of microorganisms. Additionally, compound 2-CF₃ substituted exhibited promising and selective anticancer activity through apoptosis induction, supported by gene and protein level evidence. Full article

A new series of 6-arylaminoflavones was synthesized via the Buchwald–Hartwig cross-coupling reaction, aiming to functionalize the flavone core efficiently. Reaction optimization revealed that Pd₂(dba)₃/XantPhos with Cs₂CO₃ in toluene provided the best yields, with isolated yields ranging from 8% to 95%, depending on the arylamine structure. Steric hindrance and electron-withdrawing groups at the arylamine ring impacted the reaction outcomes. Cytotoxicity assays in different human cancer cell lines indicated that substitution patterns at both the arylamine and B-rings strongly impacted biological activity. In particular, compounds bearing a 3,4-dimethoxy substitution at the B-ring and a trifluoromethyl (13c) or chlorine (13g) group at the aniline moiety exhibited enhanced cytotoxicity. These findings provide insights into the structure–activity relationship of 6-arylaminoflavones while contributing to the development of synthetic methodologies for functionalized flavones. Full article

Background/Objectives: Leukemia is a common cancer that arises in both children and adults when bone marrow’s hematopoietic stem cells proliferate unrestrained because of anomalies in normal cell regulatory systems. The present study focused on biological evaluation of oxazole-based oxadiazole scaffolds to evaluate the anti-proliferative effect on leukemic cancer cell lines. Methods: All novel oxazole-based oxadiazole scaffolds were synthesized and structurally characterized via ¹³C NMR, ¹H NMR, and HREI-MS. In order to identify an efficient anti-leukemia agent, the biological profiles of each compound were evaluated in comparison to the reference drug, Etoposide (IC₅₀ = 10.50 and 15.20 μM). Results: Analog 6 substituted with p-CF₃ at phenyl ring was identified with excellent inhibition against the HL-60 and PLB-985 cancer cell lines, with IC₅₀ of 8.50 and 12.50 μM. Through hydrogen bond formation, the trifluoromethyl moiety of analog 6 interacts with target tyrosine kinase enzyme (PDB-ID:4CSV). The interactive character of active ligands with target enzyme was demonstrated by molecular docking. The rate of inhibition in contrast with the drug concentration was also tested to check the inhibition percentage and inhibitor type via enzyme kinetics. Furthermore, the enzyme–ligand complex was also investigated via MD simulation along with pharmacophore modeling. DFT calculations were used to estimate the lead compounds’ relative stability and reactivity. According to ADMET investigation, there is safe toxicological profile for these compounds. Conclusions: The current study suggests that the potent compounds have significant anti-proliferative potential, and with further in vivo validation, hold promise for future optimization as potential leukemia treatments. Full article

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article