Search Results (20)

This paper introduces the nitration process of obtaining the synthetic intermediate 1-(2-chloro-4-fluoro-5-nitrobenzene)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one of pyraclostrobin using raw materials fluorobenzotriazolone, fuming nitric acid, fuming sulfuric acid, and toluene. The exothermic characteristics of the nitration, quenching, extraction, and alkali washing in the nitration reaction were studied, and the thermal decomposition risk of the raw materials and the secondary decomposition risk of the products in the nitration process were evaluated. The results showed that the thermal decomposition risk of the four raw materials was level 1. The acceptable level of runaway reaction in the nitration process was evaluated to be level 2, the acceptable level of runaway reaction in the quenching was level 3, the acceptable level of runaway reaction in the extraction and the alkali washing was level 1, the process hazard level of the nitration reaction and the quenching was evaluated to be level 5, and the process hazard level of the extraction and the alkali washing was level 1. Based on the comprehensive assessment results, targeted risk mitigation and control strategies are proposed to ensure process safety. Full article

The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of para-quinone methides (p-QMs) with Me₃SiRf (Rf = CF₂H, CF₃, CF₂CF₃, CF₂COOEt, and CF₂SPh) under mild conditions are described. Although Me₃SiCF₂H shows lower reactivity than Me₃SiCF₃, it can react with p-QMs promoted by CsF/18-Crown-6 to give structurally diverse difluoromethyl products in good yields. The products can then be further converted into fluoroalkylated para-quinone methides and α-fluoroalkylated diarylmethanes. Full article

Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics. More specifically, we find that the chemical structure of a DMFO and the binding mode of its difluoroacetylhydrazide derivative are crucial in determining the predominant hydrolysis mechanism. Our findings provide additional insights into two different mechanisms of DFMO hydrolysis, thus contributing to a better understanding of the HDAC6 inhibition by oxadiazoles in disease modulation and therapeutic intervention. Full article

A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel–Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp²)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope. Full article

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family of enzymes due to its complex domain organization and cytosolic localization. Experimental data point toward the therapeutic use of HDAC6-selective inhibitors (HDAC6is) for use in both neurological and psychiatric disorders. In this article, we provide side-by-side comparisons of hydroxamate-based HDAC6is frequently used in the field and a novel HDAC6 inhibitor containing the difluoromethyl-1,3,4-oxadiazole function as an alternative zinc-binding group (compound 7). In vitro isotype selectivity screening uncovered HDAC10 as a primary off-target for the hydroxamate-based HDAC6is, while compound 7 features exquisite 10,000-fold selectivity over all other HDAC isoforms. Complementary cell-based assays using tubulin acetylation as a surrogate readout revealed approximately 100-fold lower apparent potency for all compounds. Finally, the limited selectivity of a number of these HDAC6is is shown to be linked to cytotoxicity in RPMI-8226 cells. Our results clearly show that off-target effects of HDAC6is must be considered before attributing observed physiological readouts solely to HDAC6 inhibition. Moreover, given their unparalleled specificity, the oxadiazole-based inhibitors would best be employed either as research tools in further probing HDAC6 biology or as leads in the development of truly HDAC6-specific compounds in the treatment of human disease states. Full article

Elaborating on the residual fate of fluxapyroxad and its metabolites based on their nationwide application was vital to protect the human population from their hazardous effects. In this study, a rapid and sensitive analytical method was developed to trace fluxapyroxad and two of its metabolites in peanut matrices using an ultrahigh chromatography method coupled with mass spectrometry (UHPLC–MS/MS) within 3.5 min. The occurrence, pharmacokinetic degradation and terminal magnitudes of fluxapyroxad were reflected in the original deposition of 8.41–38.15 mg/kg, half–lives of 2.5–8.6 d and final concentrations of 0.004–37.38 mg/kg in peanut straw. The total concentrations of fluxapyroxad in peanut straw (0.04–39.28 mg/kg) were significantly higher than those in peanut kernels (<0.001–0.005 mg/kg) and an obvious concentration effect was observed in fresh (0.01–11.56 mg/kg) compared dried peanut straw (0.04–38.97 mg/kg). Fluxapyroxad was demethylated to 3–(difluoromethyl)–N–(3′,4′,5′–trifluoro[1,1′–biphenyl]–2–yl)–1H–pyrazole–4–carboxamide (M700F008, 0.02–5.69 mg/kg) and further N–glycosylated to 3–(difluoromethyl)–1–(ß–D–glucopyranosyl)–N–(3′,4′,5′–triflurobipheny–2–yl)–1H–pyrzaole–4–carboxamide (M700F048, 0.04–39.28 mg/kg).The risk quotients of the total fluxapyroxad for the urban groups were significantly higher than those for the rural groups, and were both negatively correlated with the age of the groups, although both acute (ARfD%, 0.006–0.012%) and chronic (ADI%, 0.415–1.289%) risks are acceptable for the human population. The high-potential health risks of fluxapyroxad should be continuously emphasized for susceptible toddlers (1–3 years), especially those residing in urban areas. Full article

CF₂H moiety has a significant potential utility in drug design and discovery, and the incorporation of CF₂H into biologically active molecules represents an important and efficient strategy for seeking lead compounds and drug candidates. On the other hand, quinoxalin-2-one is of great interest to pharmaceutical chemists as a common skeleton frequently occurring in plenty of natural products and bioactive compounds. Herein, we reported a practical and efficient protocol for the synthesis of 3-CF₂H-quinoxalin-2-ones. Thus, in the presence of 3 mol% of photocatalyst and S-(difluoromethyl)sulfonium salt as difluoromethyl radical sources, a wide range of quinoxalin-2-ones readily underwent a visible-light redox-catalyzed difluoromethylation reaction, to deliver structurally diverse 3-difluoromethyl-quinoxalin-2-ones. We believe that this would facilitate increasing chances and possibilities for seeking potential lead compounds and drug candidates and further boost the development of fluorine-containing pharmaceuticals. Full article

In this study, 32 novel quinazolinone-scaffold-containing pyrazole carbamide derivatives were designed and synthesized in a search for a novel fungicide against Rhizoctonia solani. Single-crystal X-ray diffraction of 3-(difluoromethyl)-N-(2-((6,7-difluoro-4-oxoquinazolin-3(4H)-yl)methyl)phenyl)-1-methyl-1H-pyrazole-4-carboxamide (6a₁₁) confirmed the structure of the target compounds. The in vitro antifungal activity of the target compounds against R. solani was evaluated at 100 µg/mL. The structure–activity relationship analysis results revealed that antifungal activity was highest when the substitution activity was at position 6. Moreover, the position and number of chlorine atoms directly affected the antifungal activity. Further in vitro bioassays revealed that 6a₁₆ (EC₅₀ = 9.06 mg/L) had excellent antifungal activity against R. solani that was higher than that of the commercial fungicide fluconazole (EC₅₀ = 12.29 mg/L) but lower than that of bixafen (EC₅₀ = 0.34 mg/L). Scanning electron microscopy), 7.33 (SEM) revealed that N-(2-((6,8-dichloro-4-oxoquinazolin-3(4H)-yl)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (6a₁₆) also affected the mycelial morphology. The findings revealed that molecular hybridization was an effective tool for designing antifungal candidates. Meanwhile, pyrazolecarbamide derivatives bearing a quinazolinone fragment exhibited potential antifungal activity against R. solani. Full article

A reagent-controlled highly stereoselective reaction between (S)-difluoromethyl phenyl sulfoximine 1 and imines is reported, and this synthetic method provides a variety of enantiomerically enriched α-difluoromethyl amines. The main pros of this approach include high efficiency, high stereoselectivity, and a broad substrate scope, which is probably achieved through a non-chelating transition state. Full article

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its molecular packing is stabilized by F···H, N···H and O···H hydrogen bonds, π···π stacking and C–O···π intermolecular interactions. Moreover, AIM, NCI and Hirshfeld analysis evidenced that azido moiety has a significant role in the stabilization of crystal packing through weak intermolecular interactions, where analysis of electronic density suggested closed-shell (CS) interatomic interactions. Full article

A convenient synthetic approach to previously unknown NH-iminophosphonates bearing 2-, 3-, and 4-pyridyldifluoromethyl groups at the imine carbon atom was developed. The synthetic potential of these novel building blocks was demonstrated by their conversion into highly functionalized acyclic and heterocyclic aminophosphonates and phosphonic acids combining in their structure biorelevant aminophosphonic fragment, difluoromethyl group, and pyridyl, piperidyl, thiazolidin-4-one, or thiazidinan-4-one heterocyclic moieties in a single molecular platform. Full article

The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC₅₀ = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC₅₀ = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (M^pro). Moreover, due to the high similarity between hCoV-229E M^pro and SARS-CoV-2 M^pro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E M^pro and promising in terms of energy of binding and docking pose. Full article

A routine synthesis was performed to furnish the title compound which incorporates a versatile difluoromethyl group on the aniline substitution of a 4-anilinoquinoline kinase inhibitor motif. In addition, the small molecule crystal structure (of the HCl salt) was solved, which uncovered that the difluoromethyl group was disordered within the packing arrangement and also a 126.08(7)° out of plane character between the respective ring systems within the molecule. The compound was fully characterized with ¹H/¹³C-NMR and high-resolution mass spectra (HRMS), with the procedures described. Full article

The ¹⁸F-labeling of CF₂H groups has been recently studied in radiopharmaceutical chemistry owing to the favorable nuclear and physical characteristics of the radioisotope ¹⁸F for positron emission tomography (PET). Following up on the reported efficiency of the [¹⁸F]difluoromethyl benzothiazolyl-sulfone ([¹⁸F]1) as a ¹⁸F-difluoromethylating reagent, we investigated the influence of structurally-related [¹⁸F]difluoromethyl heteroaryl-sulfones in the reactivity toward the photoredox C–H ¹⁸F-difluoromethylation of heteroarenes under continuous-flow conditions. In the present work, six new [¹⁸F]difluoromethyl heteroaryl-sulfones [¹⁸F]5a–[¹⁸F]5f were prepared and, based on the overall radiochemical yields (RCYs), three of these reagents ([¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]5f) were selected for the fully automated radiosynthesis on a FASTlab^TM synthesizer (GE Healthcare) at high level of starting radioactivity. Subsequently, their efficiency as ¹⁸F-difluoromethylating reagents was evaluated using the antiherpetic drug acyclovir as a model substrate. Our results showed that the introduction of molecular modifications in the structure of [¹⁸F]1 influenced the amount of fac-Ir^III(ppy)₃ and the residence time needed to ensure a complete C–H ¹⁸F-difluoromethylation process. The photocatalytic C–H ¹⁸F-difluoromethylation reaction with the reagents [¹⁸F]5a, [¹⁸F]5c, and [¹⁸F]5f was extended to other heteroarenes. Radical-trapping experiments demonstrated the likely involvement of radical species in the C–H ¹⁸F-difluoromethylation process. Full article

Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3′-(difluoromethyl)-4′-methoxycinnamoyl amides using Deoxofluor^® as a fluorinating agent. The N-isopropyl, N-isopentyl, and N-(2-phenylethyl) amides 11b, 11d and 11g were the most active and selective against Mycobacterium smegmatis (MIC = 8 µg/mL) with 11b and 11g displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of N-isopropylamide 11b were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards M. smegmatis, changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards M. smegmatis makes them potential leads in the search for new narrow spectrum antibiotics against M. tuberculosis. Full article