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The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1H NMR, 13C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins. [ABSTRACT FROM AUTHOR]

N-phenyl benzohydrazonoyl halide derivatives are important building blocks in the synthesis of a large number of heterocyclic compounds that include pyrazoles, pyridazine, etc. The main factor in the importance of hydrazonyl halide is the easy release of the nitrile imine when treated in an alkaline medium through the preparation process. Owing to the wide range of applications of these precursors, we will introduce a general overview for the synthesis and reactions of these types of compounds. [ABSTRACT FROM AUTHOR]

Both pyrazole and coumarin moiety are important scaffolds for their natural occurrences as well as a broad spectrum of pharmaceutical properties. When coumarin fuses with pyrazole containing a diverse functionality, synergic effect may be observed in the field of medicinal and material chemistry. Owing to their various functionality on the pyrazole as well as coumarin moiety of the title compounds, they possess fantastic biological properties including antimicrobial, antiproliferative, CpIMPDH inhibition, α-glucosidase inhibition, selective hCA IX inhibition as well as anticancer activities. Some architectural pyrazolo[c]coumarin derivatives were reported to be used in bipolar host materials and blue TADF-OLEDs. For these reasons, a special attention has been paid to researchers for the searching of new, greener and efficient protocols for the design and synthesis of pyrazolo[c]coumarins to evaluate their biological activities. This paper reviews the research data in the literature on the synthetic strategies for structurally designed pyrazolo[c]coumarin derivatives. Furthermore, the biological properties of these synthesized compounds are described by highlighting their mode of interactions with different cells and enzymes. [ABSTRACT FROM AUTHOR]

This research delves into the uncharted territory of pyrazole derivatives as potential antidepressants, despite their versatile biological activities. The study primarily focuses on a novel antidepressant designed as a selective serotonin reuptake inhibitor (SSRI) and involves the synthesis of six new pyrazole derivatives through a conventional heating method. These compounds were then subjected to pharmacokinetic prediction and molecular docking studies at the active site of the human serotonin transporter protein enzyme (PDB ID: 5I73) using AutoDock Vina 1.2.3. SwissADME software was utilized to forecast pharmacokinetics, while PreADMET software assessed toxicity. The findings suggest that these derivatives exhibit promising antidepressant properties in comparison to established drugs. The convergence of docking, SwissADME, and toxicity results implies potential avenues for the development of effective antidepressants based on pyrazole derivatives, thereby shedding light on a novel class of compounds with potential applications in mental health treatment. [ABSTRACT FROM AUTHOR]

In the present work, a well organised pathway for the eco‐friendly synthesis of a series of 4,5‐diarylpyrazole‐1‐carboxylates has been reported. The resulted compounds were characterized by different spectroscopic techniques (IR, 1H‐NMR & 13C‐NMR and HRMS). To shed light on various properties of interests, density functional theory (DFT) was utilized to optimize the ground state geometry of synthesized pyrazoles. Time dependent density functional theory (TDDFT) was used to investigate the impact of various functionals on the absorption wavelength i.e., B3LYP, M062X, BHandHLYP, B3P86, CAM‐B3LYP, and PBE0. Among all these functional, CAM‐B3LYP and BHandHLYP were in good consent with the experimental results. With an aim to enhance the optoelectronic properties, 10 new derivatives were designed by varying the various substituents on the aryl ring. Among all these synthesized pyrazole molecule, Methyl 4‐(4‐Methoxyphenyl)‐5‐(3‐nitrophenyl)‐1H‐pyrazole‐1‐carboxylate 3a and Methyl 4‐(4‐Methoxyphenyl)‐5‐(4‐nitrophenyl)‐1H‐pyrazole‐1‐carboxylate 3b exhibited better optoelectronic properties with HOMO‐LUMO gap of 3.38 eV. To the best of our knowledge, the studies of photophysical properties of these 1,4,5‐trisubstituted pyrazoles for optoelectronic uses has been reported first time by our research group. [ABSTRACT FROM AUTHOR]

Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their C═C bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential B─N/C─N bond formation is described. The reaction starts with the addition of LBRs (Lewis base–boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron‐handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research. [ABSTRACT FROM AUTHOR]

This review mainly focused on the synthesis of 3(5)-trifluoromethylpyrazoles via condensation of trifluoromethyl-β-diketones with hydrazines. Also, a special emphasis is led on the biological potential of fluorine containing compounds and pyrazoles in introduction section. We have covered all the literature reported condensation reactions of trifluoromethyl-β-diketones with hydrazines. [ABSTRACT FROM AUTHOR]

AbstractThe novel N-naphthylcyanoacrylamide thioglycosides 4 were readily prepared by the reaction of N-napthylcyanoacetamide 1 with aryl isothiocyanates in the presence of potassium hydroxide, followed by coupling of the produced salts 2 with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galacto-pyranosyl bromides 3. The N-naphthyl acrylamide thioglycoside 12 was prepared by the reaction of N-napthylcyanoacetamide 1 with glucose isothiocyante 10 in the presence of potassium hydroxide, followed by alkylation of the produced salt 11 with methyl iodide. The reaction of thioglycoside compounds 4 with hydrazines afforded the corresponding naphthyl-pyrazole hybrids. [ABSTRACT FROM AUTHOR]

To tune the complexation and solvent extraction performance of the ligands with a 1,10-phenanthroline core for trivalent actinides (An3+) and lanthanides (Ln3+), we synthesized two new asymmetric tetradentate ligands with pyrazole and amide groups, i.e., L1 (N,N-diethyl-9-(5-ethyl-1H-pyrazol-3-yl)-1,10-phenanthroline-2-carboxamide) and its analogue L2 with longer alkyl chains (N,N-dihexyl). The complexation of the ligands with Ln3+ was confirmed by 1H NMR titration and X-ray crystallography, and stability constants were measured in methanol by spectrophotometric titration. The asymmetric ligands exhibited an improved performance in terms of selective solvent extraction of Am3+ over Eu3+ in strongly acidic solutions compared to their symmetric analogues. The improved selectivity of the asymmetric ligands was interpreted theoretically by density functional theory simulations. This study implies that combining different functional groups to construct asymmetric ligands may be an efficient way to tune ligand performance with regard to An3+ separation from Ln3+. [ABSTRACT FROM AUTHOR]

A novel Zn dipyrazolate metal‐organic framework (MOF), Zn(azbpz) (azbpz2−=4,4′‐azobis(3,5‐dimethylpyrazolate), has been synthesized and structurally characterized using micro‐crystal electron diffraction. The framework contains chain‐type secondary building units comprised of tetrahedral Zn2+ ions bridged by pyrazolate groups, resulting in guest‐accessible channels lined with methyl and azo functional groups. CO2, C2H2, C2H4, C2H6, C3H6, and C3H8 gas adsorption isotherms were measured to investigate the potential of Zn(azbpz) as an adsorbent for selective separation of binary gas mixtures. The data reveal selective adsorption of acetylene over CO2, and column breakthrough experiments demonstrate good performance for C2H2/CO2 separation. [ABSTRACT FROM AUTHOR]

3-Alkyl-5-(diethylaminomethyl)pyrazoles reacted with chloroacetyl chloride to give 1-chloroacetyl derivatives which were subjected to heterocyclization with thiobenzamide, thiourea, and N-phenylthiourea in the presence of triethylamine in ethanol. As a result, previously unknown 3-alkyl-5-(diethylaminomethyl)-1-(1,3-thiazol-4-yl)-1H-pyrazoles were synthesized. [ABSTRACT FROM AUTHOR]

New 1,3-disubstituted 2,2-dimethylcyclopropanes of the isoxazole and pyrazole series were synthesized starting from (+)-3-carene. Olefination of the reductive ozonolysis product of (+)-4-acetyl-2-carene produced 1R-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane, further reaction of which with hydroxylamine or hydrazines led to heterocyclic compounds. It was shown that 3,5-dimethylpyrazoles could be synthesized on the surface of Al2O3 using ultrasonic irradiation. Studies of the antimicrobial activity of heterocyclic derivatives of dibromovinyl-2,2-dimethylcyclopropane found significant fungicidal effects of pyrazoles 8, 10, and 11 with weak antibacterial activity. [ABSTRACT FROM AUTHOR]

Nitrogen‐centered radicals are versatile synthetic intermediates with the ability to undergo diverse reactions. However, the utility of these reactive species in NN coupling reactions, especially in nitrogen‐rich heterocycles, remains a significant challenge due to the high electronegativity of the nitrogen atoms and the poor molecular stability of high‐nitrogen compounds. In this work, the possibility of NH bond cleavage in different functionalized pyrazoles to produce corresponding nitrogen‐centered radicals was investigated through density functional theory calculations. Based on the calculated results, the NN bridged 4c and 4e were synthesized with expected reaction efficiencies, which were further analyzed by frontier molecular orbital theory. Furthermore, the molecular stability of the synthesized NN bridged bipyrazoles was also studied. [ABSTRACT FROM AUTHOR]

In the structure of the title compound, C19H19N3O5S·C4H8O2, the two independent dioxane molecules each display inversion symmetry. The pyrazole ring is approximately parallel to the aromatic ring of the oxy-ethanone group and approximately perpendicular to the tolyl ring of the sulfonyl substituent. An extensive system of classical and 'weak' hydrogen bonds connects the residues to form a layer structure parallel to (201), within which dimeric subunits are conspicuous; neighbouring layers are connected by classical hydrogen bonds to dioxanes and by 'weak' hydrogen bonds from Htolyl donors. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G1/S phase transition. CDK-2 targeting has been shown to suppress the viability of multiple cancers. However, the exploration and application of a CDK-2 inhibitor in the treatment of glioblastoma are sparse. Methods: We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial–mesenchymal transition. Results: Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood–brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway. Conclusion: The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma. [ABSTRACT FROM AUTHOR]

N-Arylpyrazoles are important building blocks in many biologically active compounds, natural products, pharmaceuticals, and industries. It is an important moiety of various drugs and exhibits extensive biological activities viz., antibiotic, anticancer, antifungal, anti-inflammatory, anti-coagulant, analgesic, antipyretic, anti-depressant, insecticidal, and hyperglycemic activities. Various protocols have been designed for the synthesis of N-arylpyrazoles facilitated by a wide variety of metal-based catalysts at high or room temperature, metal free reactions, various named reactions, multicomponent reactions, and those occurring under different electromagnetic radiations. Various ligands are found to promote Cu-catalyzed N-arylation of pyrazole under mild conditions in short time. This review describes the synthesis and biological applications of N-arylpyrazole derivatives reported during 2019–2023.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

This document is a correction notice for an article titled "Sonochemical synthesis of benzylidene derivatives of enolizable carbonyls and their analogues in aqueous ethanol" published in the journal Research on Chemical Intermediates. The correction addresses an error in the original publication where the triple bond of the cyano (CN) group was incorrectly depicted as a quarter bond in several graphical abstracts and schemes. The correct versions of the graphical abstract and schemes have been provided in the correction notice. The correction was made by Palak J. Patel, Hiren R. Chaudhary, Vivek K. Gupta, and Divyang M. Patel. [Extracted from the article]

Nitrogen-containing organofluorine derivatives, which are prepared using fluorinated building blocks, are among the most important active fragments in various pharmaceutical and agrochemical products. This review focuses on the reactivity, synthesis, and applications of fluoromethylated hydrazones and acylhydrazones. It summarizes recent methodologies that have been used for the synthesis of various nitrogen-containing organofluorine compounds.

Novel fluorescent pyrazole-containing boron (III) complexes were synthesized employing a one-pot three-component reaction of 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-aminobenzenecarboxylic acids, and boronic acids. The structures of the novel heterocyclic compounds were confirmed using 1H-, 13C-, 15N-, 19F-, and 11B-NMR, IR spectroscopy, HRMS, and single-crystal X-ray diffraction data. The photophysical properties of the obtained iminoboronates were investigated using spectroscopic techniques, such as UV–vis and fluorescence spectroscopies. Compounds display main UV–vis absorption maxima in the blue region, and fluorescence emission maxima are observed in the green region of the visible spectrum. It was revealed that compounds exhibit fluorescence quantum yield up to 4.3% in different solvents and demonstrate an aggregation-induced emission enhancement effect in mixed THF–water solutions.

We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized chronic lymphocytic leukemia (CLL) studies. Patients (≥65 years) with previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5-0.8 mg/kg ≤12 cycles (n = 133). With up to 8 years of follow-up (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI], 0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 31 patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials were registered at www.clinicaltrials.gov as #NCT01722487 and #NCT01724346.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

Sickle cell disease (SCD) is characterized by the production of sickle hemoglobin (HbS), which when deoxygenated, polymerizes leading to red blood cell damage and hemolytic anemia, a defining feature of SCD. Voxelotor (Oxbryta) is a small molecule inhibitor of HbS polymerization that disrupts the polymerization mechanism by binding HbS to increase HbS oxygen affinity. Voxelotor is approved in the United States for the treatment of SCD in patients greater than or equal to 12 years of age at a 1500 mg once-daily (q.d.) dose. These exposure-response analyses aimed to evaluate the relationships between voxelotor whole blood concentration and change from baseline (CFB) in clinical measures of anemia and hemolysis and between voxelotor whole blood and plasma concentrations and the incidence of selected safety end points to confirm the voxelotor mechanism of action and to support the clinical dose recommendation. In patients treated with voxelotor up to 72 weeks, CFB hemoglobin (Hb) increased linearly (p < 0.001) with increasing voxelotor concentration and percent Hb occupancy and increases in CFB Hb corresponded to improvements in measures of hemolysis. The target 1 g/dl increase in CFB Hb was achieved with 1500 mg voxelotor q.d. Significant relationships were observed between voxelotor exposures and grade greater than or equal to 1 increased alanine aminotransferase and decreased white blood cell count; however, most events were grade 1. No clinically important covariate effects on voxelotor efficacy or safety were observed. Overall, these analyses support 1500 mg q.d. as the therapeutic dose for voxelotor in adults and adolescents.

Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

IntroductionTreatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 - 100 × 109/L) are reported.Patients and methodsPatients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety.ResultsOf 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were -20.5% (-55.8% to 38.5%, n=51) and -39.8% (-98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3).ConclusionA starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

IntroductionDiabetic ketoacidosis (DKA) causes acute and chronic neuroinflammation that may contribute to cognitive decline in patients with type 1 diabetes. We evaluated the effects of agents that reduce neuroinflammation (triarylmethane-34 (TRAM-34) and minocycline) during and after DKA in a rat model.Research design and methodsJuvenile rats with DKA were treated with insulin and saline, either alone or in combination with TRAM-34 (40 mg/kg intraperitoneally twice daily for 3 days, then daily for 4 days) or minocycline (45 mg/kg intraperitoneally daily for 7 days). We compared cytokine and chemokine concentrations in brain tissue lysates during DKA among the three treatment groups and in normal controls and diabetic controls (n=9-15/group). We also compared brain inflammatory mediator levels in these same groups in adult diabetic rats that were treated for DKA as juveniles.ResultsBrain tissue concentrations of chemokine (C-C) motif ligand (CCL)3, CCL5 and interferon (IFNγ) were increased during acute DKA, as were brain cytokine composite scores. Both treatments reduced brain inflammatory mediator levels during acute DKA. TRAM-34 predominantly reduced chemokine concentrations (chemokine (C-X-C) motif ligand (CXCL-1), CCL5) whereas minocycline had broader effects, (reducing CXCL-1, tumor necrosis factor (TNFα), IFNγ, interleukin (IL) 2, IL-10 and IL-17A). Brain inflammatory mediator levels were elevated in adult rats that had DKA as juveniles, compared with adult diabetic rats without previous DKA, however, neither TRAM-34 nor minocycline treatment reduced these levels.ConclusionsThese data demonstrate that both TRAM-34 and minocycline reduce acute neuroinflammation during DKA, however, treatment with these agents for 1 week after DKA does not reduce long-term neuroinflammation.

Immune-checkpoint inhibitors (ICI) have revolutionized cancer therapy but are associated with infrequent but lethal myocarditis, for which management remains uncertain. Abatacept, a CTLA-4 fusion protein targeting CD86 on antigen presenting cells and leading to global T-cell anergy, has been described as a potential treatment in individual reports. Yet, abatacept treatment dosage, schedule and optimal combination with other immunosuppressive therapies are unclear. We describe a 25-year-old man who developed pembrolizumab (anti-PD1)-induced myocarditis 14 days after first injection for thymoma treatment, which deteriorated into cardiogenic shock, with sustained ventricular arrhythmia, requiring urgent extracorporeal life support implantation, despite prompt initiation of corticosteroids and mycophenolate-mofetil. Using a strategy of serial measurement ensuring with a target of >80% CD86 receptor occupancy on circulating monocytes, abatacept dose was adjusted and combined with ruxolitinib and methylprednisolone. This strategy resulted in high-dose of abatacept: 60 mg/kg in three doses (20 mg/kg each) within the first 10 days, followed by two doses. Clinical improvement occurred within 7 days, with resolution of systolic cardiac dysfunction, and ventricular arrhythmias resulting in successful discharge from hospital. We reversed a case of nearly lethal ICI-myocarditis, using specific patient-dose adjusted abatacept, which may serve as basis for personalized treatment of patients with severe ICI-adverse events. Trial registration number: NCT04294771.

Metal–organic frameworks (MOFs) capable of post-synthetic metalation (PSMet) have garnered significant interest as supports for catalytic metals. The Mn-based MOF, MnMOF-1 ([Mn3(L2Me)3] where L2Me = bis-(4-carboxyphenyl-3,5-dimethylpyrazolyl)methane), has been an exemplar for studying PSMet. Herein we investigate the synthesis of Mn-based MOFs from related flexible ditopic pyrazole carboxylate links, along with the formation of MOFs with similar tetratopic hinged linkers. We show for the first time that MnMOF-1 is likely a kinetic or metastable phase and a newly identified 2D layered material (MnMOF-2D) is the thermodynamically favoured product for this metal–linker combination. Formation of a MnMOF-1 structure with shorter linkers is thwarted by steric clashes that preclude the formation of the Mn3 cluster. This observation prompted the use of density functional theory (DFT) simulations that showed the target material to be very dense, highly strained and thereby energetically unfavourable, but potentially, a hypothetical MnMOF-1 structure with a longer phenylethynyl spacer would be energetically feasible. Finally, the predominance of 2D MOFs formed with shorter flexible links encouraged us to use tetratopic hinged linkers to form 3D frameworks, which was vindicated by the successful synthesis of two new porous 3D Mn-based MOFs, MnMOF-L4 and MnMOF-L5. These results highlight that reticular synthesis of MOFs formed with flexible, non-linear linkers is challenging. [ABSTRACT FROM AUTHOR]

To develop the new analgesics, different approaches to the modification of 4‐amino‐5‐phenyl‐3‐(trifluoromethyl)pyrazoles were proposed. A series of 4‐(het)arylimino‐3‐(trifluoromethyl)‐5‐phenylpyrazoles, existing as the E‐isomer, was synthesized by condensation of the 4‐aminopyrazoles with various aldehydes. Methylation of the initial substrates occurred at the NH2 group, while alkylation with bromobutyl was successfully carried out only for NH‐pyrazole to yield 3‐ and 5‐CF3‐isomeric N‐butyl‐substituted pyrazoles. The addition of phenylisothiocyanate to 4‐aminopyrazoles allowed us to introduce a thiourea fragment into their structure. According to computer calculations, all derivatives of aminopyrazoles have an acceptable ADME profile. Using the "hot plate" test in vivo, the analgesic activity of a number of the synthesized compounds was evaluated. Introducing the phenylmethanimine fragment allows us to obtain 1‐phenyl‐N‐(5‐phenyl‐3‐(trifluoromethyl)pyrazol‐4‐yl)methan‐imine as the lead compound with the analgesic activity in 1.4–2.2 times more than effect of the initial 4‐aminopyrazole, diclofenac and metamizole. In addition, the lead compound had low acute toxicity. [ABSTRACT FROM AUTHOR]

Herein, an effective and facile synthesis of 3-(pyrazol-1-yl) succinimides is first presented through silver-catalyzed aza-Michael addition of pyrazoles to maleimides. In the presence of 5 mol% of Ag2CO3, various pyrazoles smoothly reacted with maleimides in dichloroethane at 100 °C, to generate 3-(pyrazol-1-yl) succinimides in excellent yields. Notably, 3-substituted asymmetric pyrazoles exclusively give 3-pyrazolyl succinimides in excellent yields possibly due to the steric bulk of the 3-substituent excluding the formation of addition products of N². The method can also extend to gram scale. [ABSTRACT FROM AUTHOR]

Among well-studied and actively developing compounds are polyoxometalates (POMs), which show application in many fields. Extending this class of compounds, we introduce a new subclass of polyoxometal clusters (POMCs) [Mo12O28(μ-L)8]4− (L = pyrazolate (pz) or triazolate (1,2,3-trz or 1,2,4-trz)), structurally similar to POM, but containing binuclear Mo2O4 clusters linked by bridging oxo- and organic ligands. The complexes obtained by ampoule synthesis from the binuclear cluster [Mo2O4(C2O4)2(H2O)2]2− in a melt of an organic ligand are soluble and stable in aqueous solutions. In addition to the detailed characterization in solid state and in aqueous solution, the biological properties of the compounds on normal and cancer cells were investigated, and antiviral activity against influenza A virus (subtype H5N1) was demonstrated. [ABSTRACT FROM AUTHOR]

The Meyer–Schuster Rearrangement (MSR) is a challenging process for propargylic alcohols bearing fluorine atom(s) on their chains. Most classical reagents/catalysts failed to perform the MSR but, after extensive screening, we demonstrated that phosphomolybdic acid was the first efficient catalyst for the MSR with such derivatives. The scope and limitations have been studied, affording fluorine‐containing enones as useful intermediates for the synthesis of targets with fluorine(s) on their side chains. It was exemplified by the preparation of a 2‐piperidino‐pyrimidine and a pyrazole. [ABSTRACT FROM AUTHOR]

We report herein the syntheses of original pyrazolines and pyrazoles through 1,3‐dipolar cycloaddition of cyclic enones with 2,5‐disubstituted nitrile imines achieved via photochemical activation of 2,5‐diaryl substituted tetrazoles. Monitoring of the reactions, similar to nitrile imine‐mediated tetrazole‐ene cycloadditions (NITEC), could be performed by means of UV‐vis absorption and emission measurements. The presence or absence of substituents in the alpha position of the ketone function makes it possible to direct these reactions towards the selective formation of pyrazoles or pyrazolines. The choice of the cyclic enones and 2,5‐disubstituted tetrazoles proved crucial for the fluorescence properties of the polycyclic derivatives obtained. [ABSTRACT FROM AUTHOR]

A group of compounds containing pyran, pyrazole, and pyranopyrazole were synthesized (2–4) using a facile and convenient protocol. The structure of the synthesized compounds was elucidated by spectroscopic and elemental analysis. In vitro antimicrobial evaluation was also performed for all synthesized derivatives against human pathogenic bacterial strains such as Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis using chloramphenicol as a reference. It was depicted that compounds 3d, 4b displayed a high degree of inhibition against Bacillus subtilis and Staphylococcus aureus. Compounds 2d, 4f and 2d, 4e, 4f, and 4e had high inhibition effects against Escherichia coli and Pseudomonas aeruginosa, respectively. The molecular docking study was performed against S. aureus bacteria to rationalize the binding affinities and the feasible modes of interaction with the active site of tyrosyl-tRNA synthetase. It was found that the synthesized compounds were well fit into the binding site of tyrosyl-tRNA synthetase. The obtained results were in good accordance with the experimental data. The data obtained were promising candidates for further development of novel heterocyclic scaffolds as therapeutics with high efficacy biomedical precursors. [ABSTRACT FROM AUTHOR]

Design and synthesis of three novel series of aryl enaminones (3a–f and 5a–c) and pyrazole (4a-c) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO2 hydrase assay. Enaminone sulphonamide derivatives (3a–c) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2–63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC50 = 4.918 and 12.27 µM, respectively) and hypoxic (IC50 = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC50 = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC50 = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells. [ABSTRACT FROM AUTHOR]

The Hantzsch reaction created a new series comprising 1,4-dihydropyridine pyrazoles and oxa diazoles (DHP) by initially synthesizing DHP esters, then its carbohydrates, and subsequent treatment with hydrazine. Pyrazole derivatives (Am1 and Am2) were obtained via the reaction of hydrazines with acetylacetone or ethyl acetoacetate, whereas the oxadiazole derivative (Am3) was prepared via reaction with carbon disulfide in an alkaline medium. The prepared compounds were identified using spectroscopic techniques (FTIR, ¹H and 13C NMR, and mass spectrometry). The anti-breast cancer activity of new compounds was evaluated. This cytotoxicity activity afforded that compound (AS) was the strongest in this group together with an IC50 = 100.24µg mL-1, whereas compound (AT) demonstrated the lowest potency, with an IC50 value of 300 µg mL-1. The Hantzsch reaction was used in the synthesis of a new 1,4-dihydropyridine that has pyrazole and oxadiazole moieties. The activity of in vitro cytotoxicity (MTT cell viability assay) was determined. In vitro MCF7 cells were used in the evaluation of the cytotoxicity activity (MTT cell viability assay) of new compounds. This cytotoxicity activity meant that compound (AS) was the strongest in this group, with an IC50 of 100.24 µg mL-1, while compound (AT) had the least potency, with an IC50 value of 300 µg mL-1. Based on our findings, we can infer that 1,4-dihydropyridine derivatives (DHPs) are noteworthy heterocyclic compounds with pharmacological potential.  This cytotoxicity activity meant that compound (AS) was the strongest in this group, with an IC50 of 100.24 µg mL-1, while compound (AT) had the least potency, with an IC50 value of 300 µg mL-1.  [ABSTRACT FROM AUTHOR]

To enhance the combustion performance of composite solid propellants (CSPs), a series of ferrocene‐based pyrazole energetic compounds were prepared and characterized systemically by spectroscopic techniques in this study. Moreover, their catalytic performance and mechanism as burning rate catalysts (BRCs) were investigated, and the related kinetic parameters were obtained via Flynn–Wall–Ozawa (FWO) and Kissinger–Akahira–Sunose (KAS) methods, respectively. Besides, their anti‐migration performance and mechanism were studied via simulating the aging experiments of propellant samples at different times. The results showed that these compounds exhibited excellent catalytic effect on the thermal decomposition of ammonium perchlorate, which is a vital oxidizer in CSPs and determines its combustion performance. Among them, EMFc‐1 showed the best catalytic performance because of the higher content of active component. The pyrolysis temperature of ammonium perchlorate was reduced by 56.2 °C and the heat release was increased by 248.2 J g−1 with 5 wt% EMFc‐1 as catalyst. Moreover, their anti‐migration performance was improved greatly compared with the commercial catocene (Cat) and ferrocene. The work indicates that these compounds can be applied as BRCs to enhance the combustion performance of propellants. [ABSTRACT FROM AUTHOR]

The ligand environment of the cluster complex is modified by a reaction of the cluster with Br2 in N,N-dimethylformamide at room temperature, which results in bromination of all pyrazole and pyrazolate ligands at the fourth position and in bromide ligand substitution for apical pyrazole. The solvent effect on ligand bromination is considered. The cluster complex crystallizes in the tetragonal symmetry (space group P4/n) and forms infinite layers via hydrogen bonds between the terminal 4-bromopyrazole ligands and the bromine anion. The complex also demonstrates reversible one-electron reductions of the cluster core shifted relative to the initial compound by 30 mV and 90 mV towards larger potentials. [ABSTRACT FROM AUTHOR]

The molecular crystals of monomeric and dimeric pyrazole complexes were prepared via one‐pot syntheses. These are dichloridobis(3,5‐dimethyl‐1H‐pyrazole‐κN1)cobalt/zinc(0.2/0.8), [Co0.20Zn0.80Cl2(C5H8N2)2] or [Co0.2Zn0.8Cl2(3,5‐dmp)2] (1), and bis(μ‐3,5‐dimethyl‐1H‐pyrazole)‐κ2N1:N2;κ2N2:N1‐bis[bromido/chlorido(0.7/0.3)bis(3,5‐dimethyl‐1H‐pyrazole‐κN1)cobalt/zinc(0.1/0.9)], [Co0.20Zn1.80Br1.40Cl0.60(C5H7N2)2(C5H8N2)2] or [Co0.1Zn0.9Br0.7Cl0.3(μ‐3,5‐dmp)(3,5‐dmp)]2 (2). The isolated complexes contain 3,5‐dimethylpyrazole (3,5‐dmp) ligands formed in situ from the decomposition of 1‐hydroxymethyl‐3,5‐dimethylpyrazole. In both isolated complexes, some positional disorder is observed at the metal ions and halogen ligands. The molecular crystals of 1 and 2 are centrosymmetric, with the space groups C2/c and P, respectively. Additionally, in the dinuclear complex, the pyrazole ring has a bridging coordination function with respect to the metal ions. Both complexes have good biological activities against cancer cells. The results of an in vitro cytotoxicity study indicated that compounds 1 and 2 showed significant cytotoxicity for cancer cell lines, including hepatic (HepG2 cells), lung (A549 cells) and colon cancer cells (SW 480 and SW 620). Based on the calculated IC50 values against human cancer cell lines, it was found that both complexes demonstrated potent antiproliferative activity combined with great selectivity towards cancer cells. Complex 2 was a more effective cytotoxic agent which, at the same time, exhibited high cytocompatibility. The obtained data are very encouraging and could be useful for anticancer drug discovery. [ABSTRACT FROM AUTHOR]

A one-pot, two-step route is proposed for the synthesis of Benzopyrano[2,3-c]pyrazoles by using salicylaldehydes (1), malononitrile (2) and phenyl hydrazines (3) as substrates and Rhodamine-B as an organophotoredox catalyst in acetonitrile under 23 W CFL irradiation as a source of visible light. Rhodamine- B is a basic red xanthene dye which is extremely water soluble. The utilization of an efficacious, environmentally benign, cost effective and feasible methodology to form C–O and C–N bond via generation of several free radicals after that intramolecular cyclization, are the distinctive traits of this procedure. In addition to this, some other aspects like short reaction time, greener approach and adaptability towards a broad array of substrates, with good to excellent yield of the product further augment the synthesis. [ABSTRACT FROM AUTHOR]

The ligand environment of the cluster complex is modified by a reaction of the cluster with Br2 in N,N-dimethylformamide at room temperature, which results in bromination of all pyrazole and pyrazolate ligands at the fourth position and in bromide ligand substitution for apical pyrazole. The solvent effect on ligand bromination is considered. The cluster complex crystallizes in the tetragonal symmetry (space group P4/n) and forms infinite layers via hydrogen bonds between the terminal 4-bromopyrazole ligands and the bromine anion. The complex also demonstrates reversible one-electron reductions of the cluster core shifted relative to the initial compound by 30 mV and 90 mV towards larger potentials. [ABSTRACT FROM AUTHOR]

A novel series of compounds are synthesized N-(2-methyl-4-oxoquinazolin-3(4H)-yl)-3- oxo-3-(3,5-diphenyl-2H-pyrazol-1(5 H)-yl) propenamide (3a-l). All the synthesized compounds are characterized by different spectral tools 1HNMR, IR, 13CNMR, and MASS. It was screened as in vitro anticancer and antibacterial activity. Among the synthesized compounds 3d and 3e exhibit potent against three cancer cell-line MCF7, PC-3, HT-29. IC50(µM) 3d (16.52, 13.24, 10.15 µg/mL) 3e (17.28, 15.26, 12.33 µg/mL) with standard drugs doxorubicin (15.29, 12.26, 9.06 µg/mL) and 5-fluorouracil (16.15, 13.73, 10.25 µg/mL). Antibacterial activity 3d, 3e, 3j, 3k scaffolds exhibit a promising activity with the standard drug ciprofloxacin. Insilico molecular docking is examined, Its predicted a good binding affinity against with 5C5S, 6XXN, 3K46 proteins. [ABSTRACT FROM AUTHOR]

A versatile, operationally simple, temperature-dependent, and transition metal-free one-pot protocol has been devised for the preparation of novel phenanthrene-fused pyrazoles. Notably, the overall process involved an intermolecular condensation, an intramolecular 1,3-dipolar cycloaddition, and an aromatization sequence starting from biaryl-2,2′-aldehydes bearing enoate esters with various hydrazine hydrochlorides. Notably, the sequential one-pot three-component operation has also been achieved. Importantly, it was also shown that this protocol was amenable to hydroxylamine hydrochloride as the nitrogen source and furnished phenanthrene-fused isoxazoles. Notably, the temperature dependent nature of this protocol was also demonstrated, which led to the formation of dealkoxylcarbonylated phenanthrene-fused pyrazoles at slightly higher temperatures and longer reaction times. Remarkably, this metal-free protocol effectively constructed two C–N bonds and one C–C bond and exhibited a broad substrate scope. [ABSTRACT FROM AUTHOR]

A novel simple and effective method has been developed for constructing pyrazolothiadiazine and pyrazolothiadiazepine fused heterocycles incorporating an endocyclic sulfonamide fragment. The cyclocondensation of readily available N‐(chlorosulfonyl)imidoyl chlorides, RC(Cl)=NSO2Cl (R=CCl3, CF2Br), with N‐methyl‐substituted 4‐ or 5‐aminopyrazoles results in the formation of isomeric pyrazolothiadiazine‐S,S‐dioxides. Additionally, when 5‐ or 3‐aminoalkyl‐substituted pyrazoles are employed, they serve as 1,4‐N−C−C−C binucleophiles, leading to the synthesis of novel pyrazolothiadiazepine heterocycles. Notably, the trichloromethyl and bromodifluoromethyl substituents in these compounds can be converted into dichloromethyl and difluoromethyl groups, providing enhanced functionalization options. [ABSTRACT FROM AUTHOR]

The present study involves synthesis a new series of α-aminophosphonates 2a-f and 4a-d derivatives in good yield with a simple workup via Kabachnik-Fields reaction in the presence of lithium perchlorate as Lewis acid catalyst. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data. The in vitro anticancer activities of each compound were evaluated against colorectal carcinoma Colon cancer (HCT-116) and Epdermoid carcinoma (HEP2) and also Human lung fibroblast normal cell line (WI38) compared with Doxorubicin. The results showed that Compounds 2a, 4b and 4d exhibited more potent inhibitory activity for Epdermoid Carcinoma (HEP2) compared with doxorubicin. For colon carcinoma cells (HCT-116) Compounds 2a, 2d and 4b gave the strongest activity among all compounds compared with doxorubicin. Moreover, all designed structures were docked into the active site of VEGFR2 and FGFR1 proteins. The result reveals that compound 2b and have the strongest inhibitory activity of the VEGFR2 and FGFR1 proteins indicating that these substances might conceivably operate as VEGFR2 and FGFR1 inhibitors and hence might take role in anticancer activities with various binding interactions. The 3D-QSAR models produced strong statistical results since they were defined by PLS factors 4 and confirmed by parameters as R2, R2 CV, Stability, F-value, P-value, RMSE, Q2, and Pearson-r. [ABSTRACT FROM AUTHOR]

A strategy for the synthesis of iodo-substituted allylic pyrazoles through NIS-mediated regioselective addition of allenamides with pyrazoles is presented. This reaction proceeds rapidly, is scalable up to a gram scale, and tolerates a broad scope of substrates. Moreover, using 1,2,4-triazole as the nucleophile, the corresponding 1,2-addition product was obtained in good yield. Significantly, the products of this reaction, iodo-substituted allylic pyrazoles, could undergo coupling with phenylacetylene under Sonogashira cross-coupling conditions. [ABSTRACT FROM AUTHOR]

We report herein an unprecedented synthesis of difluoromethoxylated nitrogen‐containing heterocycles from the corresponding α‐(difluoromethoxy)ketones as versatile building blocks. Pyrazoles, isoxazoles and pyrimidines could be obtained via an enaminone intermediate, whereas in the direct reaction of α‐(difluoromethoxy)ketones with arylhydrazines, a Fischer indole synthesis was achieved. All these scaffolds, which are uncommon, or even sometimes novel, due to the directly attached emerging fluorinated group (EFG) −OCF2H, might be of high potential in life sciences and appear as an interesting alternative to more and more controversial classical fluorinated groups, such as the ubiquitous trifluoromethyl group. [ABSTRACT FROM AUTHOR]

Two kinds of heat-resistant explosives, 3,5-bis-(2,4-dinitrophenyl)-4-nitro-1H-pyrazole (1c) and 1,4-bis-(3,5-dinitropyrazolyl)-2,5-dinitrobenzene (2c), were synthesized and thoroughly characterized by elemental analysis, infrared spectroscopy, 1H and 13C NMR and high resolution mass spectrometry. The structures of 1c and 2c were confirmed by single-crystal X-ray diffraction and analyzed using different computing software (Multiwfn, Gaussian 09W, Diamond 3.0 and CrystalExplorer). In addition, we also investigated the thermal stabilities of these compounds by differential scanning calorimetry (DSC). 1c (Td = 352 °C) and 2c (Td = 321 °C) showed excellent thermal stabilities. The detonation properties were calculated using the EXPLO5 v6.05.04 program. The results revealed that 2c (D = 8304 m s−1, P = 30.1 GPa) showed a higher detonation velocity and pressure than the widely used heat-resistant explosive 2,2′,4,4′,6,6′-hexanitrostilbene (HNS: D = 7612 m s−1, P = 24.3 GPa). Furthermore, impact sensitivity and friction sensitivity tests revealed that 1c and 2c (IS > 40 J, FS > 360 N) were insensitive. Combining the above results, these compounds have the potential to become heat-resistant energetic materials. [ABSTRACT FROM AUTHOR]