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UNLABELLED: We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for NTRK-positive solid tumors in academic cancer centers remains largely unknown. OBJECTIVE: To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with NTRK-positive solid tumors treated at US academic cancer centers. METHODS: This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an NTRK fusion-positive (NTRK1, NTRK2, NTRK3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, NTRK testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate. RESULTS: In total, 6 centers contributed data for 55 patients with NTRK-positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to NTRK testing was 85 days (IQR = 44-978). At the time of NTRK testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). NTRK1 fusions were most common (45%), followed by NTRK3 (40%) and NTRK2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive NTRK test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies. CONCLUSIONS: This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy.

BACKGROUND: Atopic dermatitis (AD), a highly pruritic, inflammatory skin disease, affects approximately 7% of adolescents globally. A topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor, demonstrated safety and efficacy among adolescents/adults in two phase 3 studies (TRuE-AD1/TRuE-AD2). OBJECTIVE: To describe safety and efficacy of 1.5% ruxolitinib cream versus vehicle and long-term disease control of ruxolitinib cream among adolescents aged 12-17 years from pooled phase 3 study data. METHODS: Patients [≥ 12 years old with AD for ≥ 2 years, Investigators Global Assessment score (IGA) 2/3, and 3-20% affected body surface area (BSA) at baseline] were randomized 2:2:1 to ruxolitinib cream (0.75%/1.5%) or vehicle for 8 weeks of continuous use followed by a long-term safety (LTS) period up to 52 weeks with as-needed use. Patients originally applying vehicle were rerandomized 1:1 to 0.75%/1.5% ruxolitinib cream. Efficacy measures at week 8 included IGA treatment success (IGA-TS; i.e., score of 0/1 with ≥ 2 grade improvement from baseline), ≥ 75% improvement in Eczema Area and Severity Index (EASI-75), and ≥ 4-point improvement in itch numerical rating scale (NRS4). Measures of disease control during the LTS period included IGA score of 0 (clear) or 1 (almost clear) and percentage affected BSA. Safety was assessed throughout the study. RESULTS: Of 1249 randomized patients, 245 (19.6%) were aged 12-17 years. Of these, 45 patients were randomized to vehicle and 92 patients to 1.5% ruxolitinib cream. A total of 104/137 (75.9%) patients continued on 1.5% ruxolitinib cream in the LTS period [82/92 (89.1%) continued on 1.5% ruxolitinib cream; 22/45 (48.9%) patients on vehicle were reassigned to 1.5% ruxolitinib cream], and 83/104 (79.8%) of these patients completed the LTS period. At week 8, substantially more patients who applied 1.5% ruxolitinib cream versus vehicle achieved IGA-TS (50.6% versus 14.0%), EASI-75 (60.9% versus 34.9%), and NRS4 (52.1% versus 17.4%; P = 0.009). The mean (SD) reduction in itch NRS scores was significantly greater in patients applying 1.5% ruxolitinib cream versus vehicle from day 2 [- 0.9 (1.9) versus -0.2 (1.4); P = 0.03]. During the LTS period, mean (SD) trough steady-state ruxolitinib plasma concentrations at weeks 12/52 were 27.2 (55.7)/15.5 (31.5) nM. The percentage of patients achieving IGA score of 0 or 1 was sustained or further increased with 1.5% ruxolitinib cream; mean affected BSA was generally low (< 3%; i.e., mild disease). Through 52 weeks, application site reactions occurred in 1.8% of adolescent patients applying 1.5% ruxolitinib cream at any time; no patients had serious adverse events. There were no serious infections, malignancies, major adverse cardiovascular events, or thromboembolic events. CONCLUSIONS: Meaningful anti-inflammatory and antipruritic effects were demonstrated with 1.5% ruxolitinib cream in the subset of adolescent patients with AD, comparable with those observed in the overall study population; long-term, as-needed use maintained disease control and was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03745638 (registered 19 November 2018) and NCT03745651 (registered 19 November 2018).

First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.

BACKGROUND: This post-hoc retrospective study describes long-term patient-reported outcomes (PROs) for REarranged during Transfection (RET)-altered non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC), and tumor agnostic (TA) patients (Data cut-off: January 2023) from the LIBRETTO-001 trial. PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Patients with MTC also completed a modified version of the Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The proportion of patients with improved, stable, or worsened status after baseline was reported. PROs were summarized at 3 years (cycle 37) post-baseline for the NSCLC and MTC cohorts, and at 2 years (cycle 25) post-baseline for the TC and TA cohorts. Time-to-event outcomes (time to first improvement or worsening and duration of improvement) were reported. RESULTS: The baseline assessment was completed by 200 (63.3%), 209 (70.8%), 50 (76.9%), and 38 (73.1%) patients in the NSCLC, MTC, TC, and TA cohorts, respectively. The total compliance rate was 80%, 82%, 70%, and 85%, respectively. Approximately 75% (NSCLC), 81% (MTC), 75% (TC), and 40% (TA) of patients across all cohorts reported improved or stable QLQ-C30 scores at year 3 (NSCLC and MTC) or year 2 (TC and TA) with continuous selpercatinib use. Across cohorts, the median time to first improvement ranged from 2.0 to 19.4 months, the median duration of improvement ranged from 1.9 to 28.2 months, and the median time to first worsening ranged from 5.6 to 44.2 months. The total compliance rate for the mSTIDAT was 83.7% and the proportion of patients with MTC who reported diarrhea on the mSTIDAT was reduced from 80.8% at baseline to 35.6% at year 3. CONCLUSIONS: A majority of patients with RET-driven cancers improved or remained stable on most QLQ-C30 domains, demonstrating favorable health-related quality of life as measured by the QLQ-C30 during long-term treatment with selpercatinib.

Comprehensive Summary Herein, an unprecedented nickel‐catalyzed regioselective hydroalkynylation of unsymmetrical internal alkynes was realized with steric hindered resistance selectivity via the cyano‐directing group strategy. Significantly, the resulting 1,3‐enyne products could be effectively employed in the synthesis of novel nitrogen‐containing tricyclics compounds, that provided the potential candidate compound 8a (IC50 = 2.6—6.1 μmol/L) for the anti‐tumor cell proliferation activity. Therefore, this work not only improves the transition‐metal‐ catalyzed hydroalkynylation strategy of internal alkynes, but also exhibits versatility of 1,3‐enynes in the construction of the complex bioactive chemical space. [ABSTRACT FROM AUTHOR]

A wide range of α-aryl-α-diazophosphonates were easily prepared via modified diazo transfer reaction. Benzylphoshonates reacted with tosyl azide (TsN3) in the presence of potassium tert -butoxide (KO t Bu) to afford diazophosphonates in yields up to 93% (generally 70–80%). Aryldiazophosponates were successfully explored for the synthesis of 5-aryl-substituted pyrazol-3-carboxylates in one pot by the 1,3-dipolar cycloaddition with alkyl acrylates followed by NaH treatment. The second stage led to elimination of the diethoxylphosphoryl moiety with the aromatization of cycle. [ABSTRACT FROM AUTHOR]

The condensation of 1,3‐diketones with hydrazine to access 4H‐pyrazoles is a well‐established synthetic route that travels through a 4H‐pyrazol‐1‐ium intermediate. In the route to a 3,5‐diphenyl‐4H‐pyrazole containing a cyclobutane spirocycle, density functional theory calculations predict, and experiments show that the protonated intermediate undergoes a rapid 1,5‐sigmatropic shift to form a tetrahydrocyclopenta[c]pyrazole. Replacing the 3,5‐diphenyl groups with 2‐furanyl groups decreases the calculated rate of the 1,5‐sigmatropic shift by 6.2 × 105‐fold and enables the isolation of new spirocyclic 4H‐pyrazoles for click chemistry. [ABSTRACT FROM AUTHOR]

A novel Rh‐catalyzed three‐component synthesis of N‐(o‐alkylaryl) pyrazoles via cascade pyrazole annulation and aryl C‐H conjugate addition to alkenes has been developed with enaminones, hydrazines, and functionalized alkenes as starting materials. The raw materials used in this reaction are simple, cheap, and readily available, and the reactions feature excellent step economy by furnishing products via the formation of a pyrazole ring and a key C‐H activation in one‐step operation. Moreover, the reaction proceeds smoothly under air atmosphere, making it easy to operate. [ABSTRACT FROM AUTHOR]

The in vitro antifungal, antibacterial, and antioxidant activities of a substituted pyrazole derivative (FHM) have been evaluated in the current work. The addition of 4-methylpiperidin-4-ol, which increases the molecule's lipid solubility and speeds up absorption by increasing its rate of absorption, gives the molecule strong in vitro antifungal and antibacterial properties. Additionally, it is clear from the findings of structure-activity relationship (SAR) investigations. Additionally, the ab-intio technique was used to theoretically evaluate the photophysical characteristics of produced substances. Using the DFT-B3LYP-6-31G(d) basis set, the ground state optimization and HOMO-LUMO energy levels are computed. Global chemical reactivity and descriptive characteristics are evaluated using theoretically estimated HOMO-LUMO values, and the results demonstrate that the synthesized molecule possesses a high electrophilicity and electronegative index. Overall findings indicate that substituting a 4-methylpiperidin-4-ol substituted pyrazole derivative shows good photophysical and in vitro biological applications. [ABSTRACT FROM AUTHOR]

The escalating incidence of bacterial resistance to commonly prescribed antibiotics underscores the urgent need for the rapid development of innovative antibacterial medications. Heterocyclic compounds, particularly nitrogen‐containing heterocycles like pyrazoles and thiazoles, have garnered attention for their diverse biological activities, including antimicrobial properties. Here, we present a green and efficient multicomponent synthesis method for fourteen novel benzothiazole‐tethered pyrazole derivatives. Utilizing the deep eutectic solvent glycerol/K2CO3 as a base‐catalytic reaction medium at 70 °C, this synthesis approach yielded promising compounds exhibiting substantial antimicrobial activity against various pathogenic microorganisms such as Staphylococcus aureus, Bacillus cereus, and Candida albicans. Among these, 4‐(benzo[d]thiazol‐2‐yl)‐3‐(4‐nitrophenyl)‐1‐phenyl‐1H‐pyrazol‐5‐amine emerged as the most promising candidate, showcasing significant inhibitory potentials with CZD values of 24 mm, 21 mm, and 26 mm for S. aureus, B. cereus, and C. albicans, respectively. Molecular docking studies further supported the experimental observations, revealing the high binding affinity of the compound to the nitroreductase enzyme with a binding score of −8.5 kcal/mol. These findings underscore the potential of these synthesized compounds as antimicrobial agents and suggest avenues for future research in exploring their structure‐activity relationships and therapeutic applications in combating bacterial infections. [ABSTRACT FROM AUTHOR]

The pyrazole ring structure is extensively spotted as a pharmacophore and fortify‐cation of the modern organic synthesis toolbox, which demands synthetic tactics to generate its derivatives. Especially, pyrazolo‐pyrimidinones are crucial part to synthesize phosphodiesterase type 5 (PDE5) such as sildenafil and lodenafil. Herein, we report a simple and efficient route for Sildenafil and derivatives from easily available materials. [ABSTRACT FROM AUTHOR]

We studied the reaction of N‐alkyl(aryl)pyrazoles with silylformamidine 1 that exists in an equilibrium with its carbene form via migration of the trimethylsilyl group from the carbon to nitrogen atom. The carbene insertion proceeded at the C−H group in 5th position. N‐alkyl(aryl)pyrazoles featuring substituents such as Br, CN and NO2 group reacted readily affording the corresponding aminals. This approach allowed us to synthesize pyrazole dialdehyde and phosphine featuring a vicinal aldehyde group. The reaction does not require any catalyst. The insertion position was unambiguously confirmed by X‐ray analysis of an aminal and a set of derivatives. Aminals hydrolysis afforded the corresponding pyrazole carbaldehydes. Methanolysis of the aminals gave N‐methylimines of the pyrazolecarbaldehydes. Highly acidic nitro pyrazole instead of the insertion underwent silylation in 5th position. [ABSTRACT FROM AUTHOR]

Chemical reactivity and applications of 4-alkynylated pyrazol-3-ones are described. A facile access to the synthesis of novel pyrazol-4-yl furan- and/or thiophene-2-carboxylates through the ring transformation and subsequent acylation of 4-alkynylated pyrazol-3-ones as the key intermediates, which were prepared from pyrazole-4,5-dione and terminal alkynes, in moderate to good yields is achieved. All the synthesized compounds were characterized by spectroscopic analysis. [ABSTRACT FROM AUTHOR]

The very limited number of structurally known thionitrosyl complexes of technetium was increased by the synthesis of [TcII(NS)Cl3(PPh3)2] (3) and [TcII(NS)Cl3(PPh3)(OPPh3)] (4) and their reaction products with hydrotris(pyrazolyl)borates, {HB(pzR)3}−. Similar reactions were conducted with [TcI(NO)Cl2(PPh3)2(CH3CN)] and related rhenium thionitrosyls. Remarkably, most such reactions result in a rapid cleavage of the boron–nitrogen bonds of the ligands and the formation of pyrazole complexes of the two group 7 metals. Only one compound with an intact {HB(pzR)3}− ligand could be isolated: the technetium(I) complex [TcI(NO)Cl(PPh3){HB(pz)3}] (2). Other products show the coordination of one or four neutral pyrazole ligand(s) in the coordination spheres of technetium generated by thermal decomposition of the pyrazolylborates [TcI(NO)Cl2(PPh3)2(pzH)] (1) and [TcI(NS)Cl(pzHMe2)4]+ (5). Reactions with the corresponding thionitrosylrhenium complex [ReII(NS)Cl3(PPh3)2] require higher temperatures and only compounds with one pyrazole ligand, [ReI(NS)Cl2(PPh3)(pzHR)] (6a–6c), were isolated. The products were studied spectroscopically and by X-ray diffraction. [ABSTRACT FROM AUTHOR]

In this study, the magnetic Mg0.5Zn0.375Ni0.125Fe2O4 nanoparticle was prepared by the co-precipitation method and characterized with various methods, such as FT-IR, XRD, TGA, FESEM, EDX, and VSM. The catalytic activity of this magnetic nanocatalyst was perused in synthesizing dihydropyrano[2,3-c] pyrazole and tetrahydrodipyrazolopyridines derivatives. To indicate some of this paper's preponderances, preparing a novel heterogeneous magnetic nanocatalyst with high reactivity produces high-yield and purity products. Moreover, the synthesized nanocatalyst has advantages such as high catalytic activity, non-toxicity, short reaction time, easy separation from the reaction mixture using an external magnet, and reusability several times without significant loss in its catalytic activity. [ABSTRACT FROM AUTHOR]

The reactivity of imidazole, pyrazole, 1,2,4‐triazole, 1,2,3‐triazole, and tetrazole with acetone (propan‐2‐one) has been studied by 1H and 13C NMR using acetone‐d6 as solvent at temperatures ranging from 173 to 300 K at 10 K intervals. Simultaneously, the reaction has been theoretically calculated at the B3LYP/6‐311++G(d,p) level, and experimental and theoretical results have been compared. The equilibrium constants between azoles and adducts α,α‐dimethyl‐azole‐methanol were analyzed, assuming that the straight part of the plots –R ln Ke vs. 1/T can be used to determine ΔH and ΔS. Calculated and experimental data are related, but the theoretical values are proportionally higher. The tautomerism of triazoles and tetrazole has been considered in order to discuss the reactions. [ABSTRACT FROM AUTHOR]

In order to obtain acaricides of pyrazole acrylonitrile with better acaricidal activity for mitecontrol, seventeen novel ester derivatives were synthesized via four steps of Blanc chloromethylation reaction, dehalogenation reaction, condensation reaction and esterification reaction using ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate as the starting material. Furthermore, their acaricidal activity against Tetranychus cinnabarinus was assessed by immersion test, and the mortality rate and lethal midrange concentration LC50 were calculated. The results show that the target compounds display excellent acaricidal activity against T. cinnabarinus, and compared with the commercial pesticide cyenopyrafen (LC50 = 0.61 mg/L), compounds 5q and 5k possess significantly higher acaricidal activity against T. cinnabarinus with LC50 values of 0.17 and 0.22 mg/L, respectively. [ABSTRACT FROM AUTHOR]

In this Communication, we comprehensively investigated substituent effects relevant to iterative reversible activation fragmentation chain transfer (RAFT) single unit monomer insertion (SUMI) reactions. Through the use of the pyrazole carbodithiolate (PCDT) "Z-group" as the chain transfer component in RAFT SUMI, we show the importance of "Z-group" effects and its interplay with "R-group" (the carbon-centred radical precursor) effects. We also expanded the scope of RAFT SUMI to new monomer types and sequences thereof. As such, the C–S bond dissocation/reformation steps were found to be crucial factors in SUMI, and it was found that general substituent effects must be wholistically examined for every step of this reaction. This stands in contrast with conventional knowledge of RAFT polymerisation, where the main consideration is often centred around the propagation stage, i.e., the key C–C bond formation step. Indeed, contrary to SUMI, the latter characteristic was observed in the analogous alternating copolymerisation. [ABSTRACT FROM AUTHOR]

We report an efficient [3+2] cycloaddition protocol for the synthesis of pyrazolo[1,2‐a]pyrazolones from Morita‐Baylis‐Hillman adducts and N,N'‐cyclic azomethine imines. The R‐BINOL chiral phosphoric acid was identified as the suitable catalyst for the reported cycloaddition protocol. Almost all MBH adducts regioselectively delivered 7‐oxo‐pyrazolo[1,2‐a]pyrazoles at an efficient yield of 69–91 %. With exception, the MBH adducts derived from acrylonitrile deliver 5‐oxo‐pyrazolo[1,2‐a]pyrazoles comparatively at a higher yield than the 7‐oxo‐pyrazolo[1,2‐a]pyrazoles. The density functional theory (DFT) studies demonstrate that the reaction is thermodynamically more feasible in the presence of R‐BINOL chiral phosphoric acid. [ABSTRACT FROM AUTHOR]

Precise modification of a chemical site in a molecule at the single-atom level is one of the most elegant yet difficult transformations in chemistry. A reagent specifically designed for chemoselective introduction of monoatomic carbon is a particularly formidable challenge. Here, we report a straightforward, azide-free synthesis of a crystalline and isolable diazophosphorus ylide, Ph3PCN2, a stable compound with a carbon atom bonded to two chemically labile groups, triphenylphosphine (PPh3) and dinitrogen (N2). Without any additives, the diazophosphorus ylide serves as a highly selective transfer reagent for fragments, including Ph3PC, to deliver phosphorus ylide–terminated heterocumulenes and CN2 to produce multisubstituted pyrazoles. Ultimately, even exclusive carbon-atom transfer is possible. In reactions with aldehydes and acyclic and cyclic ketones (R2C=O), the carbon-atom substitution forms a vinylidene (R2C=C:) en route to alkynes or butatrienes. [ABSTRACT FROM AUTHOR]

Novel library of pyrazole derivatives (6a–k) from substituted 4-dioxaborolanyl-1H-pyrazole and halo benzaldehyde through simultaneous Suzuki reaction, nucleophilic addition, and hydrolysis under moderate reaction conditions. The desired compounds 6a–k have been formed in good to high yield. All the compound structures were characterized by analytical and spectral (1H NMR,13C NMR and MS) studies. Furthermore, the evaluation of biological activity of synthesized molecules. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An electrochemical protocol for synthesizing tetra‐substituted sulfonated pyrazoles is developed. The notable feature of this method is the electrocatalytic generation of an active iodine species, which enables the direct use of 1,3 dicarbonyls as the reactant and also eliminates the necessity for external electrolytes. A wide range of functionalities are compatible under the electrocatalytic condition, resulting good to excellent production of the desired pyrazole derivatives. Detailed synthetic and electrochemical studies enlighten the electrocatalytic pathway. [ABSTRACT FROM AUTHOR]

Inspired by the enzyme acetylene hydratase, we investigated the reactivity of acetylene with tungsten(II) pyrazole complexes. Our research revealed that the complex [WBr2(pz-NHCCH3)(CO)3] (pz = 3,5-dimethyl-pyrazolate) facilitates the stochiometric reaction between pzH and acetylene to give N-vinyl-pz. This vinyl compound readily hydrolyzes to acetaldehyde, mirroring the product of acetylene hydration in the enzymatic process. The formation of the vinyl compound likely involves a reactive intermediate complex where acetylene acts as a two-electron donor, in contrast to isolable acetylene complexes that are inert to nucleophilic attack by water. Results suggest an alternative mechanism for the enzyme, including vinylation of a neighboring amino acid by acetylene in the active site prior to hydration. [ABSTRACT FROM AUTHOR]

An efficient palladium‐catalyzed three‐component reaction for the synthesis of tricyclic fused 1,2,3‐triazole derivatives from amino‐NH‐1,2,3‐triazoles, isocyanide and iodoarenes has been developed, involving three new bonds formation by one manipulation in moderate to good yields with excellent functional group tolerance. Moreover, it is also suitable for other N‐heterocyclic substrates including pyrazole, imidazole, indole, tetrazole and its derivatives. [ABSTRACT FROM AUTHOR]

The main building blocks for the production of flavonoids and iso-flavonoids are chalcones. Chalcones are α, β-unsaturated carbonyl compounds containing three carbons. The condensation products of aromatic aldehydes with acetophenones in the presence of a catalyst are called chalcones. Numerous techniques and plans have been documented for the synthesis of these substances. Aldol condensation and Claisen–Schmidt condensation continue to hold a prominent position among all. Chalcones and their derivatives have a broad range of pharmacological activities due to presence of reactive α,β-unsaturated carbonyl group. Numerous chalcone-heterocycle hybrids seem to show promise as potential medication candidates based on a review of the literature because of their comparable or better activity than the standards. As a result, the creation and development of novel, highly effective therapeutic medications based on previously established techniques may benefit from this review. [ABSTRACT FROM AUTHOR]

The synthesis of 2-(benzo[d]thiazol-2-yl)-N-arylacetamide derivatives was achieved by cyclocondensation reaction of 2-aminothiophenol and different cyanoacetamide derivatives in solvent free condition and without any catalyst. The resultant products were used as a precursor for synthesis novel acetamide, acrylamide, pyrazole and pyridine derivatives via reaction with different reagents. All reaction products have been tested for their antioxidant activities compared with ascorbic acid. Some on novel synthesized products furnished promising results. [ABSTRACT FROM AUTHOR]

A method for targeted structural modification of the methyl ester of phlomisoic acid was developed by introduction of an additional C-16 ketopyrazole moiety via cyclocondensation of diterpenoid alkyne-1,2- diones with arylhydrazines. The conditions for regioselective formation of labdanoid 1,3-diarylpyrazol-5- ylmethanones were found. The possibility of a sequential four-component reaction in a single pot was demonstrated. Significant analgesic activity of labdanoid-substituted diarylpyrazoles in thermal and chemical irritation models was established. [ABSTRACT FROM AUTHOR]

The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine–Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent yields (up to 97%) and high enantioselectivities (up to 98.5% ee) under mild reaction conditions. In addition, this protocol was further expanded to synthesize highly enantioenriched hybrid molecules bearing biologically relevant heterocycles.

The metal-free direct oxidative cross-dehydrogenative C–H bond amination of imidazopyridines with pyrazole in water as solvent has been developed under K2 S2 O8-promoted mild conditions. This strategy was applied to variable imidazoheterocycles to give amination products in moderate to good yields. The described protocol also offers scale-up synthesis for the construction of C–N bonds, which makes it suitable for the synthesis of biologically active compounds and pharmaceuticals. [ABSTRACT FROM AUTHOR]

A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NH4SCN/KSeCN as thio/selenocyanogen sources and PhICl2 as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl–SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.

This report detailed the synthesis of multi‐substituted pyrazoles through the acceptorless dehydrogenative coupling (ADC) reaction catalyzed by a well‐defined manganese(I)‐pincer complex. Symmetrically substituted pyrazoles were synthesized by reacting 1,3‐diols with hydrazines. Unsymmetrically substituted pyrazoles were selectively made via the ADC of primary alcohols with methyl hydrazones. Water and hydrogen are liberated as the green byproducts. The endurance of these methodologies has been presented by producing 30 substrates with varied functionalities. Model reactions were scaled up to demonstrate practicability. The reaction rate and order were measured to transparent the involvement of the reagents during catalysis. Control experiments elucidated the plausible reaction mechanisms. [ABSTRACT FROM AUTHOR]

We have developed a straightforward electrochemical protocol for direct α-amidation and α-pyrazolation of N-alkoxy- and N-aryloxycarbonyl pyrrolidines with amides or pyrazoles. Unlike previously reported methods, this protocol does not require pre-prepared amidation reagents, thereby shortening the synthesis route and boosting atom economy. Various functional groups are tolerated, and the reaction proceeds at room temperature in only 2.5 h without assistance from chemical oxidants or catalysts. [ABSTRACT FROM AUTHOR]

Regioselective C6‐arylation of thieno[3,2‐c]pyrazoles with aryl iodides as coupling partners has been developed. This strategy was performed in the presence of Pd(OAc)2 as catalyst in combination with AgOTf as an oxidant and TFA in dimethylacetamide. In all experiments, only the C6‐arylated thieno[3,2‐c]pyrazole was isolated since its C5‐regioisomer was not observed, indicating the high regioselectivity of this approach. The catalytic system used is compatible with a variety of 3‐functionalized thieno[3,2‐c]pyrazoles and iodoaryl electrophiles, providing access to 3,6‐disubstituted thieno[3,2‐c]pyrazoles in yields ranging from 49% to 94%. [ABSTRACT FROM AUTHOR]

The catalytic asymmetric reaction of 5‐aminopyrazoles with naphthoquinone esters has been established. A wide range of unprecedented axially chiral naphthylpyrazole derivatives (29 examples) have been synthesized in moderate to excellent yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) by utilizing chiral phosphoric acid as a catalyst. This protocol features mild reaction conditions, a broad substrate scope, good scalability and facile derivatization. Moreover, preliminary mechanistic investigation was conducted to elucidate the mechanism. [ABSTRACT FROM AUTHOR]

A series of 4-hydroxy-6-methyl-3-(1-(4-(aryl/methyl)thiazol-2-yl)-1H-pyrazol-3-yl)-2H-pyran-2-ones 3a–h have been synthesized from aryl/methyl halomethylketones and a key pyrazole intermediate 1 using a convenient one-pot synthesis method. All compounds were characterized by NMR and MS, and the structure of three of them (3a, 3b and 3f) was resolved by X-ray diffraction. These heteroatom-rich thiazole compounds were then evaluated as inhibitors of Mycobacterium tuberculosis InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of the mycobacterium. Although inhibitory activities were found to be rather weak, molecular docking studies were also been carried out to understand a possible mode of interaction with key residues in the enzyme's active site. [ABSTRACT FROM AUTHOR]

In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through 1H NMR, 13C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against Mythimna separata, Tetranychus cinnabarinus, Plutella xylostella, and Aphis medicaginis at a dosage of 500 μg/mL, and some title compounds were active towards Nilaparvata lugens at 500 μg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against M. separata, T. cinnabarinus, or A. medicaginis at 100 μg/mL, with the mortalities of compounds 8a, 8c, 8d, 8e, 8f, 8g, 8o, 8s, 8v, 8x, and 8z against A. medicaginis, in particular, all reaching 100%. Even when the dosage was lowered to 20 μg/mL, compound 8s also expressed 50% insecticidal activity against M. separata, and compounds 8a, 8e, 8f, 8o, 8v, and 8x displayed more than 60% inhibition rates against A. medicaginis. The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future. [ABSTRACT FROM AUTHOR]

Metal-mediated inner-sphere N–N coupling is an uncommon route to N–N bond formation. Herein, we report a mechanistic study of pyrazole formation via oxidation-induced N–N coupling of diazatitanacycles. In TEMPO oxidation reactions, the first of two oxidations is rate limiting and TEMPO coordination to Ti is critical for reactivity. In oxidations with Fc+ salts, coordinating counteranions such (eg. Cl−) aid an "inner-sphere-like" oxidation. [ABSTRACT FROM AUTHOR]

We here reported a highly stereoselective method for the synthesis of polysubstituted conjugated dienes from α‐aryl α‐diazo alkynyl ketones and pyrazole‐substituted unsymmetric aminals under mild conditions, which was promoted by photo‐irridation and involved with 1,6‐dipolar intermediate and quadruple sigmatropic rearrangements, was successfully developed. In this transformation, the cleavage of four bonds and the recombination of five bonds were implemented in one operational step. This protocol provided a modular tool for constructing dienes from amines, pyrazoles and α‐alkynyl‐α‐diazoketones in one‐pot manner. The results of mechanistic investigation indicated that the plausible reaction path underwent the 1,6‐sigmatropic rearrangement instead of the 1,5‐sigmatropic rearrangement. [ABSTRACT FROM AUTHOR]

A straightforward protocol has been developed to access 3-selenylated pyrazolo[1,5-a]pyrimidines from readily available amino pyrazoles, chalcones, and diaryl/dialkyl diselenides. This I2-catalyzed methodology is highly useful for synthesizing a wide range of functionalized 3-(aryl/alkylselanyl)pyrazolo[1,5-a]pyrimidine derivatives. Mechanistic investigation disclosed that iodine catalysis is very important in both the cyclization process as well as in the C-H selenylation step. Moreover, the developed reaction conditions are also applicable for the cyclization of amino pyrazole with enaminone followed by C-H selenylation in one pot. The use of simple reagents and catalyst, wide substrate scope, mild and metal-free reaction conditions, and practical applicability are the attractive facets of this approach. [ABSTRACT FROM AUTHOR]

In this work, the unique performance of binary acid‐base CuO/La2O3 nanocomposite as a highly efficient heterogeneous catalyst was successfully examined for the one‐pot multicomponent synthesis of pyrano [2, 3‐c] pyrazole derivatives. The strong interactions between La and Cu had a profound effect on the catalytic activity of nanocatalysts. In addition, high selectivity, easy recovery, reusability, a very reasonable price, simple preparation and eco‐friendliness are other important advantages of this nanocatalyst. The characterized nanocomposite demonstrated excellent structural and morphological properties, leading to high catalytic efficiency. Characterization using Fourier Transform Infrared Spectroscopy (FT‐IR), X‐ray Powder Diffraction (XRD) confirmed crystallographic structure, and Field Emission Scanning Electron Microscopy (FE‐SEM) showed a spherical particle size of approximately 43 nm. Energy‐Dispersive X‐ray (EDX) analysis confirmed the composition of La, O, and Cu elements in the nanocomposite as 86.4 %, 13.5 %, and 0.2 %, respectively. The optimal condition for the synthesis resulted in a 98 % yield of pyrano [2, 3‐c] pyrazole derivatives under reflux with 0.02 g of CuO/La2O3 catalyst in a 10‐minute reaction time. [ABSTRACT FROM AUTHOR]

This article discusses a catalytic strategy for the conversion of isoxazoles and oxadiazoles into pyrazoles and 1,2,4-triazoles, respectively, through a formal O-to-N exchange. The protocol utilizes catalytic amounts of an air-stable Ni(4-CF3 stb) 3 complex in combination with hydrazine. The authors demonstrate the generality of the protocol and its functional group tolerance. This research provides a potential solution for the rapid evaluation of five-membered heterocyclic scaffolds in synthetic campaigns. [Extracted from the article]

New C–N-bonded bisazoles were obtained by cine-substitution of 1,3-dinitro-1H-pyrazole-4-carbonitrile by the action of N-azoles. Their spectral characteristics were investigated using multinuclear NMR spectroscopy. [ABSTRACT FROM AUTHOR]

A fully continuous-flow nitration and post-processing protocol has been introduced into the preparation of 4-nitropyrazole. The process started from the nitration reaction of pyrazole with mixed acid, followed by continuous quenching, neutralization, extraction and separation. After the collected organic phase was rotationally evaporated to recover the solvent, the final product 4-nitropyrazole was obtained with 96.9% yield, 99.3% purity and 381 g/h productivity. By establishing a kinetics model and MATLAB simulation calculation, it worked out to achieve the preferable selectivity conditions of mono-nitration product 4-nitropyrazole. The process of post-processing solved the problems of solid precipitation and extractant hydrolysis. The extraction process was determined by the distribution coefficient and twice extraction was used to reduce the amount of organic solvent. [ABSTRACT FROM AUTHOR]

Extending the family of oxothiomolybdates, the interaction of the cyclic anion [Mo8O8S8(OH)8(C2O4)]2− and the complex [Mo4O4S4(C2O4)5]6− with organic compounds of the azole series—pyrazole (pzH) and 1,2,4-triazole (trzH) in water solution and in the melt of ligands was investigated. In water solution pyrazole plays only the role of cation (upon protonation) to form the complex (pzH2)2[Mo2O2S2(C2O4)2(H2O)2]. While in the reaction in melt of pzH in the case of the initial cyclic anion, the resulting anionic product [Mo6O6S6(pz)6(MoO4)]2− represents a pioneering example of a cyclic oxothiometalate {Mo6} anchored by the coordination of six bridging pyrazolates (pz), complemented by a MoO42− core. At the same time, the interaction of [Mo4O4S4(C2O4)5]6− with pzH and trzH melts yields the binuclear clusters [Mo2O2S2(C2O4)2L2]2−, where L = pzH or trzH. The composition and structures of the compounds were determined using a variety of physicochemical methods, including single-crystal X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Background: Pyrazole derivatives have gained attention as potential leads for developing anti-inflammatory and analgesic drugs. Chemical modifications of pyrazole structures offer a strategy to enhance their therapeutic properties, while minimizing undesirable effects. Objective: This study aimed to synthesize novel pyrazole derivatives through chemical modifications and assess their anti-inflammatory and analgesic activities. Methods: A series of pyrazole variants were synthesized by reacting various acetophenone derivatives and diethyl oxalate in basic conditions, followed by treatment with glacial acetic acid and hydrazine hydrate. The resulting compounds were further methylated and acetylated. The synthesized compounds were characterized using elemental analysis, 1H NMR, IR, and MASS spectroscopy. The anti-inflammatory activity was evaluated using the rat paw edema technique induced by carrageenan, while the analgesic activity was assessed using the writhing reflux method. Results: Among the newly synthesized pyrazole derivatives, compounds 3b, 3e and 3g′ demonstrated significant anti- inflammatory activity with reduced ulcerogenic potential. Compounds 3d,3b′ and 3d′ exhibited notable analgesic activity compared to the standard drug. The chemical modifications introduced in these derivatives were confirmed through spectroscopic analyses. Conclusion: The findings of this study highlight the potential of pyrazole derivatives as promising candidates for anti- inflammatory and analgesic drug development. The structural modifications performed in this research improved the therapeutic activities of the compounds, while addressing safety concerns. Further investigations are warranted to elucidate the underlying mechanisms of action and optimize the pharmacological profiles of these novel pyrazole derivatives. This study synthesized novel pyrazole derivatives and evaluated their anti-inflammatory and analgesic properties. Key findings showed that certain modified compounds exhibited significant therapeutic activities with reduced side effects. The results support the potential of pyrazole derivatives as effective and safer options for pain and inflammation management. [ABSTRACT FROM AUTHOR]

As a hybrid weapon, two novel series of pyrazoles, 16a‐f and 17a‐f, targeting both COX‐2 and ACE‐1‐N‐domain, were created and their anti‐inflammatory, anti‐hypertensive, and anti‐fibrotic properties were evaluated. In vitro, 17b and 17f showed COX‐2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF‐κB (IC50 1.87 and 2.03 μM, respectively). 17b (IC50 0.078 μM) and 17 f (IC50 0.094 μM) inhibited ACE‐1 comparable to perindopril (PER) (IC50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF‐κB‐p65 and P38‐MAPK expression by −0.62, −0.22, −0.53, and −0.24 folds, respectively compared to l‐NAME (−0.34, −0.45 folds decline in NF‐κB‐p65 and P38‐MAPK, respectively). 17b reduced ANG‐II expression which significantly reversed the cardiac histological changes induced by L‐NAME. [ABSTRACT FROM AUTHOR]

Objective: A novel triazolyl benzene sulfonamides were synthesized and evaluated for antitubercular and anticancer activity. Methods: Our study is dedicated to preparing highly efficient diphenyl pyrazole triazolyl benzene sulphonamides, as part of our ongoing efforts in the development of effective antitubercular and anticancer agents. The antitubercular activity was performed against the M. tuberculosis H37RV strain using a Microplate Alamar Blue Assay (MABA). The in silico pharmacokinetic profile (ADMET) and molecular docking studies were conducted using the enzyme crystal structure of Burkholderia cenocepacia dihydropteroate synthase complexed with 7,8-dihydropteroate (PDBID:2Y5S) and DHFR from Bacillus stearothermophilus (PDB ID: 1ZDR). Results and Discussion: The synthesis of eighteen novel derivatives was followed by the characterization, antitubercular, and anticancer screening of those compounds. Physical (MP and TLC) and spectral (FT-IR, 1H NMR, and MS) approaches were used to characterize the compounds. The H37RV strain was tested for antitubercular activity using the Microplate Alamar Blue Assay (MABA) method. When tested for antitubercular activity, compounds (Va), (Ve), and (VIIe) showed substantial activity at 50 µg/mL concentrations, whereas other substances showed action at 100 µg/mL concentrations. The compounds (Va), (Ve), and (VIIe) exhibit promising binding scores with DHTP and DHFR, which contributes to their efficacy as anticancer agents. The ADMET results have a positive impact on the effectiveness of the compounds. The same compounds have also demonstrated good results in the MTT assay ranging between 2 to 10 µg/mL, out of which (Va) showed strong cytotoxic activity of 1.73 µg/mL. Conclusions: The compounds were synthesized in quantitative yields and possessed antitubercular activity and anticancer activity. [ABSTRACT FROM AUTHOR]

Objective: A new series of pyrazole-3-carbaldehyde derivatives from new hydrazones by using the Vilsmeier–Haack reaction were synthesized. Pyrazoles have the characteristic qualities of the aromatic system, which are generally quite evident in their structures having insecticide, herbicide, and healthful significance as anti-inflammatory properties and antipyretic medication actions. Pyrazole compounds have a wide spectrum of bioactivity as reported in the literature, which encourages synthesis and testing of the antimicrobial activity for synthesis compounds. Methods: P-acetamido-phenol, and 2-mercaptobenzoimidazole, which used as a starting materials for synthesis pyrazole-3-carbaldehyde derivatives. The biological activity of some prepared compounds was also tested against two G-positive bacteria and two G-negative bacteria, in addition to C. albinos fungi. A molecular modeling study of some prepared compounds showed good binding strength with the target protein. Results and Discussion: Compound N-(4-((5-(4′-(4-formyl-1-phenyl-1H-pyrazole-3-carbonyl)-[1,1′-biphenyl]4-yl)-1,3,4-oxadiazol-2-yl)methoxy) phenyl)acetamide passes a good activity against Staphylococcus aurous; the compound 3-(4′-(5-(((1H-benzo[d]imidazol-2-yl)thio)methyl)-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-carbonyl)1-phenyl-1H-pyrazole-4-carbaldehyde passes good active with C. albinos. Molecular modeling was studied for the compounds prepared with human corona virus NL63, compound N-(4-((5-(4′-(4-formyl-1-phenyl-1H-pyrazole-3carbonyl)-[1,1′-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)acetamide has best docking score –181.9 kcal/mol, while compound 3-(4′-(5-(((1H-benzo[d]imidazol-2-yl)thio)methyl)-1,3,4-oxadiazol-2-yl)[1,1′-biphenyl]-4-carbonyl)-1-(4-nitroph enyl)-1H-pyrazole-4-carbaldehyde has best hydrogen-bonding with –10 kcal/mol. In general, the binding by hydrogen bonding and steric interference was high, which leads to the conclusion that the prepared compounds have an effect on the Corona virus. Conclusions: The prepared compounds have biological activity and have good binding force with the Corona virus protein NL63, thus disrupting its work, and ccording to the toxicity assessment, the synthesized compounds belong to the third class (III). [ABSTRACT FROM AUTHOR]