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The article focuses on hereditary hyperekplexia (HPX), a rare disorder characterized by exaggerated startle response and generalized muscle stiffness, often presenting in infancy. It discusses the standard treatment with clonazepam and explores the novel use of trihexyphenidyl to alleviate persistent generalized stiffness episodes in patients unresponsive to clonazepam.

The reactivity of complexes [Fe2(μ‐S2)(CO)4L2] (L=CO (1), PPh3 (2)), with lithium alkynylide reagents generated in situ, was investigated. The behavior of the S2‐bridge in these compounds depends on the substitution at the diiron core. The reaction with the hexacarbonyl derivative 1 leads to the formation of the 1,2‐dithiolene bridged complex [Fe2(μ‐SCH=C(R)S)(CO)6] (3R) while the molecule [Fe2(μ‐SH)(μ‐SC≡CR)(CO)4(PPh3)2] (5R), with an open butterfly structure, is isolated when reacting the disubstituted derivative 2. The disubstituted dithiolene complex [Fe2(μ‐SCH=C(Ph)S)(CO)4(PPh3)2] (4Ph) can only be obtained by substitution of carbonyls with PPh3 in 3R. In the presence of piperidine, 5R isomerizes into the 1,1'‐dithiolene bridged derivative 6Ph. The novel compounds 4–6 were synthesized and characterized by IR and NMR spectroscopies. X‐ray crystallographic studies of the dithiolene complexes 3Ph–4Ph allowed their structural analysis. [ABSTRACT FROM AUTHOR]

Two series of novel hybrid heterocyclic compounds that combine the imidazole ring with bioactive piperidine, morpholine or piperazine heterosystems, through a hydrazone unit, were easily obtained by two competitive pathways. Starting from 5‐amino‐4‐cyanoformimidoyl imidazoles and 1‐aminopiperidine, 4‐aminomorpholine or 1‐amino‐4‐methylpiperazine under mild acidic media led to the selective synthesis of 5‐aminoimidazole 4‐carboxamidrazones, whereas the corresponding 4‐hydrazonoyl cyanide derivatives were obtained under stronger acidic conditions. These highly functionalized imidazoles provide convenient synthetic precursors to a vast array of heterocycles with potential pharmaceutical applications. The reaction mechanisms were elucidated on the basis of experimental assays and in silico calculations. The compounds were screened against colorectal cancer HCT116‐p53 wt cell line, and significant IC50 values of 3.69 μM and 4.83 μM were obtained. [ABSTRACT FROM AUTHOR]

In this study, the inhibition effects of aniline molecules of 1-(2-Furylmethyl) piperidine-3-carboxylic acid hydrochloride (molecule 1), and 3-Chloro-4-(3,5-dimethyl-1-piperidinyl) aniline (molecule 2), which contain piperidine ring, on the enzymes of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and glutathione s-transferase (GST) were investigated. The studies of IC50 and Ki were performed for the inhibitors. All the molecules were found to be good inhibitors for the three enzymes. Molecule 2 was detected to be an effective inhibitory with Ki values of 2.9987±0.2555 for the AChE enzyme and 1.9301±0.2563 for the BChE enzyme. Molecule 1 was found to be another effective molecule with a Ki value of 4.217±0.3759 for the GST enzyme. Ethacrynic acid (EA) and tacrine (TAC) were used as positive inhibitions for enzymes of GST and cholinesterases, respectively. The studied molecules were detected to be more effective compared to the standard compounds. Additionally, enzyme inhibitor interaction was examined theoretically by molecular docking. [ABSTRACT FROM AUTHOR]

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. [ABSTRACT FROM AUTHOR]

Background: Lung cancer ranks first in both cancer incidence and mortality in China. The emergence of novel treatments for ALK-positive NSCLC led to an improvement in survival and quality of life for patients with advanced ALK mutation-positive non-small cell lung cancer (NSCLC). This study sought to assess the cost-effectiveness of 6 tyrosine kinase inhibitors (TKIs)—crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib—as first-line treatments for ALK-positive NSCLC from the perspective of the Chinese health care system. Methods: A Markov model was developed to estimate the cost-effectiveness of these 6 TKIs. In this model, ALK-positive NSCLC patients were initially simulated to receive 1 of the 6 TKIs as first-line therapy, followed by different TKIs as subsequent treatment and salvage chemotherapy as last-line treatment. Survival data were sourced from the latest published clinical trials. Costs were derived from recent national health insurance negotiations and hospital information systems of selected health care facilities. Utilities for healthy states and adverse events were obtained from the literature. One-way and probabilistic sensitivity analysis as well as scenario analysis was conducted to assess the robustness of the results. Results: Compared to ensartinib, crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib demonstrated incremental quality-adjusted life years (QALYs) of −1.13, 0.39, −0.58, −0.09, and 0.35, respectively. The corresponding incremental costs were $10 677, $33 501, −$6426, $2672, and $24 358. This resulted in ICERs of –$9449/QALY, $85 900/QALY, $11 079/QALY, $29 689/QALY and $69 594/QALY, respectively. Conclusion: Crizotinib was considered to be absolutely dominated by ensartinib. Under a willingness-to-pay threshold of $38 223/QALY, ceritinib and brigatinib were cost-effective compared with ensartinib, while lorlatinib and alectinib were not cost-effective when compared with ensartinib. Overall, brigatinib emerged as the most cost-effective treatment among all the options considered. [ABSTRACT FROM AUTHOR]

The catalytic activity of zinc(II) compounds was exploited in the nucleophilic addition of amines to nitriles to form amidines. The reaction systems comprised a Zn(II) starting material [Zn(quin)2(H2O)] (quin− = quinaldinate, an anion of quinaldinic acid), secondary cyclic amine, acetonitrile, and in some cases, methanol. Amines with additional heteroatoms in the ring (thiomorpholine, piperazine) or ring substituents (piperidine derivatives, piperazine derivatives) with different steric and electronic effects were used. The aim of the study was to determine how the nature of the amine affects the formation of amidines. Different types of Zn(II) products were obtained: mono- or diamine complexes, amidine complexes, and also an ionic compound with a protonated amine. In one case, the amidine itself crystallized. A Zn(II) complex with acetamidine was also obtained. Acetamidine was formed from acetonitrile and ammonia, which most likely originated from the hydrolysis of acetonitrile under harsh reaction conditions. The hydrolysis could terminate at the acetamide step, which was confirmed by the isolation of a cocrystal containing acetamide. In the case of piperazine (pz), a polymeric compound with the composition [Zn(quin)2(pz)]n was isolated regardless of the reaction conditions. The same coordination polymer was also observed to form in 1-methylpiperazine, 1-ethylpiperazine, and 1-acetylpiperazine reaction systems, containing piperazine as an inherent impurity. This was unambiguously confirmed by the crystal structure of a cocrystal, [Zn(quin)2(1-Acpz)2]·[Zn(quin)2(pz)]n·4CH3CN, which formed in the 1-acetylpiperazine (1-Acpz) reaction system. [ABSTRACT FROM AUTHOR]

Simple Summary: As the precursor of pepsin, Pepsinogen C (PGC) is the final product of the maturation and differentiation of gastric mucosa cells. The latest bioinformatics analysis found that PGC may play a little-known role in the carcinogenic process, but there is no relevant experimental evidence to prove the effect of PGC on the biological function of cancer cells. In our research, we found PGC may act as a tumor suppressor in the development and metastasis of gastric cancer. PGC can downregulate its interacting protein IQGAP1 and inhibit the Rho-GTPase pathway, thereby participating in the inhibition of gastric cancer cell migration and invasion. Thus, PGC has the potential to be a new therapeutic target for gastric cancer. Aim: This study systematically explored the biological effects and mechanisms of PGC on gastric cancer (GC) cells in vitro and in vivo. Method: The critical biological roles of PGC in GC were assessed via EdU staining, Hoechst staining, flow cytometry, mouse models, CCK-8, wound healing, transwell, and sphere-forming assays. The interaction study with IQ-domain GTPase-activating protein 1 (IQGAP1) was used by Liquid chromatography-mass spectrometry co-immunoprecipitation, immunofluorescence staining, CHX-chase assay, MG132 assay, and qRT-PCR. Results: PGC inhibited the proliferation, viability, epithelial–mesenchymal transition, migration, invasion, and stemness of GC cells and promoted GC cell differentiation. PGC suppressed subcutaneous tumor growth and peritoneal dissemination in vivo. The interaction study found PGC inhibits GC cell migration and invasion by downregulating IQGAP1 protein and IQGAP1-mediated Rho-GTPase signaling suppression. In addition, PGC disrupts the stability of the IQGAP1 protein, promoting its degradation and significantly shortening its half-life. Moreover, the expression levels of PGC and IQGAP1 in GC tissues were significantly negatively correlated. Conclusion: PGC may act as a tumor suppressor in the development and metastasis of GC. PGC can downregulate its interacting protein IQGAP1 and inhibit the Rho-GTPase pathway, thereby participating in the inhibition of GC cell migration and invasion. [ABSTRACT FROM AUTHOR]

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion. [ABSTRACT FROM AUTHOR]

A new type of the four-component tandem Knoevenagel—Michael reaction was discovered, which used arylaldehydes, N,N′-dimethylbarbituric acid, dimedone, and morpholine or piperidine in organic solvents or in water. The reaction proceeded under mild conditions at room temperature with the formation of a new substituted unsymmetrical polycyclic ionic scaffold in 83–98% yields. The structures of the reaction products were confirmed by X-ray diffraction analysis on the example of two compounds. The further oxidative cyclization of the Knoevenagel—Michael reaction products led to unsymmetrical substituted dihydrofurans spiro-annulated with N,N′-dimethylbarbituric acid. The structures of the synthesized compounds were confirmed by X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Objectives: Perennial allergic rhinitis (PAR) is common in Japan. Second-generation antihistamines (SGAs) are commonly used for its treatment; however, it remains unclear which SGA is the most cost-effective. Additionally, the pharmacoeconomics of Japanese Kampo shoseiryuto (which was traditionally prescribed to treat PAR in Japan) remains poorly understood. In this study, we aimed to investigate the effectiveness of various SGAs and shoseiryuto for the treatment of PAR in Japanese outpatients, from the healthcare payer's perspective. Methods: The most cost- and clinically effective SGAs were determined from a list of 6 SGAs (bepotastine, 10 mg; cetirizine, 10 mg; ebastine, 10 mg; epinastine, 20 mg; loratadine, 10 mg; and olopatadine, 5 mg) together with shoseiryuto, using the overall improvement rate through a model-based analysis. The time horizon was 28 days. Costs were determined based on the Medical Fee Index in 2020. Deterministic and probabilistic sensitivity analyses were conducted to address the uncertainty of the base-case results. Results: Overall, bepotastine (10 mg) and ebastine (10 mg) were cost-effective. Shoseiryuto was less cost-effective than ebastine (10 mg) (dominated). Ebastine (10 mg) was the most cost-effective option based on deterministic and probabilistic sensitivity analyses. Conclusions: Ebastine (10 mg) was the most cost-effective treatment strategy for PAR among the agents evaluated in this study. This insight could aid in establishing an appropriate formulary for treating PAR in hospitals and communities. [ABSTRACT FROM AUTHOR]

Stable boroxine-amine adducts comprising dative B←N bond(s) were prepared by mechanochemically-induced reactions of phenylboronic acid (PBA) and amines (pyridine, DMAP, 1Hpyrazole, piperidine, DABCO, hexamethylenetetramine, or 4,4'-bipyridine). In-situ Raman monitoring, ex-situ PXRD and DFT calculations were used for product identification. Stoichiometry of the product (3: 1, 3:2 or 6:1 adduct) was controlled by the amine structure and the molar ratio of the reactants. The 1:2 Hbonded assembly of PBA and 4,4'-bipyridine (bpy) was confirmed as an intermediate in the adduct formation for bpy. Competitive binding experiments indicated that the exchange of the amines in the 3:1 adducts follows the computed adduct stabilities that increase with the amine basicity. Following the DFT prediction, the first adduct with two different amines, DMAP and pip, bound to one boroxine moiety was isolated and structurally characterized. Results show that calculations can be used to predict possible and preferred product(s) and their spectral characteristics. [ABSTRACT FROM AUTHOR]

Linearly fused polycyclic piperidines represent common substructures in natural products and biologically active small molecules. We have devised a Pd‐catalyzed annulation strategy to these compounds that converts readily available 2‐tetralones and indanones into these scaffolds with the potential for control of both enantio‐ and diastereoselectivity. Importantly, these compounds can be chemoselectively functionalized, providing an efficient and robust methodology to these important nitrogen‐containing molecules. [ABSTRACT FROM AUTHOR]

Background: A lack of safety data on postpartum medication use presents a potential barrier to breastfeeding and may result in infant exposure to medications in breastmilk. The type and extent of medication use by lactating women requires investigation. Methods: Data were collected from the CHILD Cohort Study which enrolled pregnant women across Canada between 2008 and 2012. Participants completed questionnaires regarding medications and non-prescription medications used and breastfeeding status at 3, 6 and 12 months postpartum. Medications, along with self-reported reasons for medication use, were categorized by ontologies [hierarchical controlled vocabulary] as part of a large-scale curation effort to enable more robust investigations of reasons for medication use. Results: A total of 3542 mother-infant dyads were recruited to the CHILD study. Breastfeeding rates were 87.4%, 75.3%, 45.5% at 3, 6 and 12 months respectively. About 40% of women who were breastfeeding at 3 months used at least one prescription medication during the first three months postpartum; this proportion decreased over time to 29.5% % at 6 months and 32.8% at 12 months. The most commonly used prescription medication by breastfeeding women was domperidone at 3 months (9.0%, n = 229/2540) and 6 months (5.6%, n = 109/1948), and norethisterone at 12 months (4.1%, n = 48/1180). The vast majority of domperidone use by breastfeeding women (97.3%) was for lactation purposes which is off-label (signifying unapproved use of an approved medication). Non-prescription medications were more often used among breastfeeding than non-breastfeeding women (67.6% versus 48.9% at 3 months, p < 0.0001), The most commonly used non-prescription medications were multivitamins and Vitamin D at 3, 6 and 12 months postpartum. Conclusions: In Canada, medication use is common postpartum; 40% of breastfeeding women use prescription medications in the first 3 months postpartum. A diverse range of medications were used, with many women taking more than one prescription and non-prescription medicines. The most commonly used prescription medication by breastfeeding women were domperidone for off-label lactation support, signalling a need for more data on the efficacy of domperidone for this indication. This data should inform research priorities and communication strategies developed to optimize care during lactation. [ABSTRACT FROM AUTHOR]

Novel rhodium‐catalyzed [3+3] annulations of diazoenals and α‐amino ketones has been disclosed here. The reactivity of diazoenals has been switched from carbenoid to vinylogous NH‐insertion by altering acyclic to cyclic α‐amino ketones. In this direction, we report an efficient strategy to synthesize 1,2‐dihydropyridines (DHPs) and fused 1,4‐oxazines. Mechanistic investigation revealed that the formyl group is necessary for carbenoid [3+3] annulation and the cyclohexyl group is the dictating factor for vinylogous NH‐ insertion. The synthetic utility of 1,2‐dihydropyridines was demonstrated by synthesizing piperidine, pyrido[1,2‐a]indole, and 2‐pyridone scaffolds. Further, structural diversification of fused 1,4‐oxazines resulted in the short synthesis of hexahydroquinolin‐2(1H)‐ones, hexahydro quinolines and tetrahydroquinolinones via ring opening rearrangement and a new oxidative deformylation, respectively. [ABSTRACT FROM AUTHOR]

The reaction of ethyl 3-aryl-2-cyanoprop-2-enoates with N1,N3-bis(2-methoxyphenyl)propanedi-amide afforded previously unknown products of intramolecular heterocyclization of the primary Michael adducts, ethyl 4-aryl-2-imino-1-(2-methoxyphenyl)-5-[(2-methoxyphenyl)carbamoyl]-6-oxopiperidine-3-car-box-ylates, in 73–90% yields. The product structure was determined by IR and NMR (1H, 13C) spectroscopy. [ABSTRACT FROM AUTHOR]

Benzimidazole-based pyrrole/piperidine analogs (1–26) were synthesized and then screened for their acetylcholinesterase and butyrylcholinesterase activities. All the analogs showed good to moderate cholinesterase activities. Synthesized compounds (1–13) were screened in cholinesterase enzyme inhibition assays and showed AChE activities in the range of IC50 = 19.44 ± 0.60 µM to 36.05 ± 0.4 µM against allanzanthane (IC50 = 16.11 ± 0.33 µM) and galantamine (IC50 = 19.34 ± 0.62 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 21.57 ± 0.61 µM to 39.55 ± 0.03 µM as compared with standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Similarly, synthesized compounds (14–26) were also subjected to tests to determine their in vitro AChE inhibitory activities, and the results obtained corroborated that all the compounds showed varied activities in the range of IC50 = 22.07 ± 0.13 to 42.01 ± 0.02 µM as compared to allanzanthane (IC50 = 20.01 ± 0.12 µM) and galantamine (IC50 = 18.05 ± 0.31 µM) and varied BuChE inhibitory activities, with IC50 values in the range of 26.32 ± 0.13 to 47.03 ± 0.15 µM as compared to standard allanzanthane (IC50 = 18.14 ± 0.05 µM) and galantamine (IC50 = 21.45 ± 0.21 µM). Binding interactions of the most potent analogs were confirmed through molecular docking studies. The active analogs 2, 4, 10 and 13 established numerous interactions with the active sites of targeted enzymes, with docking scores of −10.50, −9.3, −7.73 and −7.8 for AChE and −8.97, −8.2, −8.20 and −7.6 for BuChE, respectively. [ABSTRACT FROM AUTHOR]

Introduction: To introduce a drug to the market, it's not mandatory for it to be more effective and safer than the current treatment for the same condition. Consequently, head-to-head studies between the two best treatments for the same condition are not required, and this could result in a lack of information for patients, clinicians, and decision-makers. This study aims to evaluate the presence of head-to-head studies among the drugs used for the treatment of non-small cell lung cancer (NSCLC). Methods: Taking into account the National Comprehensive Cancer Network (NCCN) guidelines updated to 2022, which list all available treatments for each NSCLC subtype, the search engine Pubmed and the platform clinicaltrials.gov were consulted to find all completed and ongoing head-to-head studies among various treatments for NSCLC. Results: Among the anti-EGFR (epidermal growth factor receptor) drugs, 7 studies were found, with 6 completed and 5 registrational for drug commercialisation. No completed study to date has compared osimertinib and afatinib. For anti-ALK (anaplastic lymphoma kinase) drugs, 7 studies were found, with 5 completed. Alectinib, brigatinib, and lorlatinib have no completed comparison studies, but all were compared with crizotinib. Among various immunotherapy-based regimens, 5 studies were found, with only 1 completed. Therapeutic regimens based on pembrolizumab, atezolizumab, or the combination of nivolumab/ipilimumab have not been compared in studies published to date. Conclusion: There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician's choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence. [ABSTRACT FROM AUTHOR]

Trichlorido(4-methylpiperidine)gold(III), [AuCl3(C6H13N)], 1, crystallizes in Pbca with Z = 8. Tribromido(4-methylpiperidine)gold(III), [AuBr3(C6H13N)], 2, crystallizes as two polymorphs, 2a in Pnma with Z = 4 (imposed mirror symmetry) and 2b, which is isotypic to 1. The Au--N bonds trans to Cl are somewhat shorter than those trans to Br, and the Au--Cl bonds trans to N are longer than those cis to N, whereas the Au--Br bonds trans to N are slightly shorter than the cis bonds. The methyl and AuX3 groups (X = halogen) occupy equatorial positions at the six-membered ring. The packing of all three structures involves chains of molecules with offset stacking of the AuX3 moieties associated with short Au...X contacts; for 1 and 2b these are reinforced by N--H...X hydrogen bonds, whereas for 2a there are no classical hydrogen bonds and the chains are interconnected by Br...Br contacts. [ABSTRACT FROM AUTHOR]

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms' exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered. [ABSTRACT FROM AUTHOR]

Previously synthesized ethyl 2-benzamido-4-(1,4-benzodioxan-2-yl)thiophene-3-carboxylates were cyclized to 2-aryl-3-aminothieno[2,3-d]pyrimidin-4(1H)-ones by the action of hydrazine hydrate. The con-densation of ethyl 2-amino-4-(1,4-benzodioxan-2-yl)thiophene-3-carboxylate with chloroacetyl chloride gave the corresponding N-substituted 2-chloroacetamide which reacted with piperidine and morpholine to produce 2-aminoacetamides, and the latter were also subjected to cyclization with hydrazine hydrate to obtain 3-amino-thienopyrimidin-4-one derivatives. The synthesized compounds were tested for antihypoxic activity. [ABSTRACT FROM AUTHOR]

Inhibition of glycoside hydrolases has widespread application in the treatment of diabetes. Based on our previous findings, a series of dihydrofuro[3,2-b]piperidine derivatives was designed and synthesized from D- and L-arabinose. Compounds 32 (IC50 = 0.07 μM) and 28 (IC50 = 0.5 μM) showed significantly stronger inhibitory potency against α-glucosidase than positive control acarbose. The study of the structure–activity relationship of these compounds provides a new clue for the development of new α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative analysis of the results of pharmacological studies on models of the conduction and terminal anesthesia, as well as acute toxicity studies of the inclusion complex of 1-methyl-4-ethynyl-4-hydroxypiperidine (MEP) with β-cyclodextrin, was carried out. A virtual screening and comparative analysis of pharmacological activity were also performed on a number of the prepared piperidine derivatives and their host–guest complexes of β-cyclodextrin to identify the structure–activity relationship. Various programs were used to study biological activity in silico. For comparative analysis of chemical and pharmacological properties, data from previous works were used. For some piperidine derivatives, new dosage forms were prepared as beta-cyclodextrin host–guest complexes. Some compounds were recognized as promising local anesthetics. Pharmacological studies have shown that KFCD-7 is more active than reference drugs in terms of local anesthetic activity and acute toxicity but is less active than host–guest complexes, based on other piperidines. This fact is in good agreement with the predicted results of biological activity. [ABSTRACT FROM AUTHOR]

Anion exchange membranes (AEMs) are key core materials in water electrolysis, requiring both high conductivity and good dimensional stability and chemical durability. In this work, a series of poly(biphenyl piperidinium) AEMs with side octadecyl groups (Q18PBP-x) are prepared through the superacid catalyzed polymerization and grafting reactions. The long hydrophobic alkyl side chains attached onto the ether-free backbone effectively improve the dimensional stability, chemical durability and ionic conductivity of the obtained AEMs at high temperature. At 80 °C, the water absorption and swelling rate of Q18PBP-30 membrane with IEC of 2.28 mmol g−1 are 47.8 and 10.8%, respectively. Its ionic conductivity is 79.4 mS cm−1 and only decrease by 6.9% after 480 h of immersion in 2 M NaOH at 80 °C. The current density of water electrolyzer assembled with representative Q18PBP-30 membrane reaches 0.53 A cm−2 in 2 M KOH at 2.1 V, and its voltage fluctuation of durability testing is only 15.8% after 480 h at the current density of 300 mA cm−2. These results suggest that grafting long hydrophobic alkyl chains on the backbone of AEMs is a promising strategy to enhance their properties for water electrolysis. [ABSTRACT FROM AUTHOR]

Background: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. Methods: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5–20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. Results: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). Conclusion: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. Trial Registration: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021). [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the effect of esketamine on the dose–effect relationship between remifentanil and the cardiovascular response to endotracheal intubation during target-controlled infusion (TCI) of propofol. Methods: Patients underwent elective gynecological laparoscopic surgery under general anesthesia with endotracheal intubation, aged 18–65 years, American Society of Anesthesiologists class I or II, 18 kg/m2 ≤ body mass index ≤ 30 kg/m2, were randomly divided into the control (group C) and esketamine groups (group E). Before anesthesia induction, group E received an intravenous injection of 0.3 mg/kg of esketamine, while group C received an equal dose of physiological saline. TCI of propofol to the effect-site concentration (EC) of 3.0 μg/mL, and then TCI of remifentanil to the effect room and intravenous injection of rocuronium 0.6 mg/kg after MOAA/S was 0. Endotracheal intubation was performed after 2 min. Dixon's modified sequential method was used, and the initial EC of remifentanil was 3.0 ng/mL. The EC of remifentanil was determined according to the intubation response of the previous patient, with an adjacent concentration gradient of 0.3 ng/mL. The EC50 and EC95 values and their 95% confidence intervals (CIs) were determined using probit regression analysis. Results: The EC50 for cardiovascular response inhibition to endotracheal intubation using remifentanil was 3.91 ng/mL (95% CI: 3.59–4.33 ng/mL) and EC95 was 4.66 ng/mL (95% CI: 4.27–6.23 ng/mL) with TCI of propofol 3.0 μg/mL. After intravenous administration of 0.3 mg/kg of esketamine, the EC50 of remifentanil was 3.56 ng/mL (95% CI: 3.22–3.99 ng/mL) and EC95 was 4.31 ng/mL (95% CI: 3.91–5.88 ng/mL). Conclusions: Combined with TCI of propofol 3.0 μg/mL for anesthesia induction, esketamine significantly reduced the EC50 and EC95 of remifentanil to inhibit the cardiovascular response to endotracheal intubation. Trial registration: The trial was registered in the Chinese Clinical Trials Registry (www.chictr.org.cn; registration number: ChiCTR2200064932; date of registration:24/10/2022). [ABSTRACT FROM AUTHOR]

Background: Anaesthetic methods and drugs with rapid onset, rapid recovery and better postoperative analgesia are more suitable for rapid recovery in obstetric anaesthesia. We formulated the following hypothesis: a combination of mepivacaine and ropivacaine could provide a longer analgesic effect and have more advantages in terms of rapid-recovery indicators. Methods: A total of 180 pregnant women scheduled to undergo elective caesarean sections were randomly assigned to three surgical groups, which received 2% mepivacaine (Group M), 2% mepivacaine + 0.75% ropivacaine (Group MR) (Volume 1:1) or 0.75% ropivacaine (Group R) through an epidural catheter. The situation of postoperative analgesia and other indicators of rapid recovery were recorded. Results: One hundred and fifty patients were included in the final analysis. Their demographic data were similar. The visual analogue scale (VAS) scores of Group MR and Group R were lower than Group M at 1 and 2 h after surgery both at rest and with movement (P < 0.05), and the time to first ambulation in Group MR (17.38 ± 2.06 h) and Group M (17.20 ± 2.09 h) was shorter than that in Group R (22.18 ± 1.74 h) (P < 0.05). Conclusion: Application of 2% mepivacaine combined with 0.75% ropivacaine for epidural anaesthesia can provide longer postoperative analgesia and earlier ambulation, these effect may be more suitable than that of 2% mepivacaine or 0.75% ropivacaine alone for caesarean section. Trial registration: This study was registered at Chinese Clinical Trial Registry (Registration number: ChiCTR 2300078288; date of registration: 04/12/2023). [ABSTRACT FROM AUTHOR]

Securinega alkaloids have intrigued chemists since the isolation of securinine in 1956. This family of natural products comprises a securinane subfamily with a piperidine substructure and norsecurinane alkaloids featuring a pyrrolidine core. From a biosynthetic perspective, the piperidine moiety in securinane alkaloids derives from lysine, whereas the pyrrolidine moiety in norsecurinane natural products originates from ornithine, marking an early biogenetic divergence. Herein, we introduce a single-atom deletion strategy that enables the late- stage conversion of securinane to norsecurinane alkaloids. Notably, for the first time, this method enabled the transformation of piperidine-based (allo) securinine into pyrrolidine-based (allo)norsecurinine. Straightforward access to norsecurinine from securinine, which can be readily extracted from the plant Flueggea suffruticosa, abundant across the Korean peninsula, holds promise for synthetic studies of norsecurinine-based oligomeric securinega alkaloids. [ABSTRACT FROM AUTHOR]

In bis(4-methylpiperidine-N)gold(I) chloride, [Au(C6H13N)2]Cl (1), the methyl groups are, as expected, equatorial at the piperidine ring, but the Au atom is axial; this is the case for all five structures reported here, as is the expected linear coordination at the Au atom. Hydrogen bonding of the form N--H...Cl-...H--N leads to inversion-symmetric dimers, which are further connected by C--H...Au contacts. Bis(4-methylpiperidine-N)gold(I) dichloridoaurate(I), [Au(C6H13N)2][AuCl2] (2), also forms inversion-symmetric dimers; these involve aurophilic interactions and three-centre hydrogen bonds of the form NH(...Cl)2. Bis(4-methylpiperidine-N)gold(I) dibromidoaurate(I), [Au(C6H13N)2][AuBr2] (3), is isotypic to 2. The 1:1 adduct chlorido(4-methylpiperidine-N)gold(I) bis(4-methylpiperidine-N)gold(I) chloride, [Au(C6H13N)2]Cl·[AuCl(C6H13N)] (4), crystallizes as its dichloromethane solvate. The asymmetric unit contains two formula units, in each of which the chloride anion accepts a hydrogen bond from the cation and from the neutral molecule, and the two Au atoms are linked via an aurophilic interaction. A further hydrogen bond leads to inversion-symmetric dimers. The asymmetric unit of bis(2-methylpiperidine-N)gold(I) chloride, [Au(C6H13N)2]Cl (5), contains two 'half' cations, in which the Au atoms lie on twofold axes, and a chloride ion on a general position. Within each cation, the relative configurations at the atoms N and C2 (which bears the methyl substituent) are R, S. The twofold-symmetric dimer involves two N--H...Cl-...H--N units and an aurophilic contact between the two Au atoms. [ABSTRACT FROM AUTHOR]

Microscopic colitis, a diagnosis under the umbrella term of inflammatory bowel disease, is a prevalent cause of watery diarrhea, often with symptoms of urgency and bloating, typically observed in older adults aged ≥ 60 years. Its incidence has been reported to exceed those of ulcerative colitis and Crohn's disease in some geographical areas. Although nonpathognomonic endoscopic abnormalities, including changes of the vascular mucosal pattern; mucosal erythema; edema; nodularity; or mucosal defects, e.g., "cat scratches" have been reported, a colonoscopy is typically macroscopically normal. As reliable biomarkers are unavailable, colonoscopy using random biopsies from various parts of the colon is compulsory. Based on the histological examination under a microscope, the disease is divided into collagenous (with a thickened subepithelial collagenous band) and lymphocytic (with intraepithelial lymphocytosis) colitis, although incomplete forms exist. In routine clinical settings, the disease has a high risk of being misdiagnosed as irritable bowel syndrome or even overlooked. Therefore, healthcare providers should be familiar with clinical features and rational management strategies. A 6–8-week oral budesonide treatment course (9 mg/day) is considered the first-line therapy, but patients often experience relapse when discontinued, or might become intolerant, dependent, or even fail to respond. Consequently, other therapeutic options (e.g., bismuth subsalicylate, biologics, loperamide, bile acid sequestrants, and thiopurines) recommended by available guidelines may be prescribed. Herein, clinically meaningful data is provided based on the latest evidence that may aid in reaching a diagnosis and establishing rational therapy in geriatric care to control symptoms and enhance the quality of life for those affected. [ABSTRACT FROM AUTHOR]

Simple Summary: Crizotinib, an oral tyrosine kinase inhibitor that targets ALK, MET, and ROS1 kinase, has emerged as an effective treatment for ROS1-rearranged NSCLC. In South Korea's real-world setting, characterized by a higher elderly population and increased brain/central nervous system metastasis rates, crizotinib remains a cornerstone in treating ROS1-rearranged NSCLC, providing lasting clinical benefits with a favorable safety profile. Liquid biopsies, utilizing biomarkers, are instrumental in detecting targetable mutations, monitoring the disease burden, and identifying resistance mechanisms. In our study, next-generation sequencing using cell-free total nucleic acids enables the detection of ROS1 fusions and the identification of resistance mechanisms during disease progression. Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74–ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib's sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies. [ABSTRACT FROM AUTHOR]

New derivatives of crown compounds were successfully prepared via multicomponent reactions of a thia‐podand, an β‐keto ester and ammonium acetate based on modifications of the Petrenko‐Kritschenko reaction. The structure of the synthesized compounds was identified by physical‐chemical methods of analysis including IR, NMR, HRMS, and single‐crystal X‐ray diffraction. In addition, an in vitro assay against the α‐glucosidase of synthetic compounds was first evaluated and showed positive results. The most active compound exhibited an IC50 value of 5.69±0.27 μM, which is 37 fold more potent than the standard drug of acarbose (IC50 208.42±4.68 μM). Furthermore, prediction of ADMET parameters revealed that almost all synthesized trithiacrown ether derivatives expressed drug‐like characteristics. Our results provide useful evidence that crown ether compounds are not only good chelators with metal ions but also scaffolds for developing lead candidates in the treatment of diabetic disease. [ABSTRACT FROM AUTHOR]

Treatment of 3-bromo-6-chloroimidazo[1,2-b]pyridazine with a variety of 1° or 2° alkylamines (2.0 equiv) with CsF (1.0 equiv), and BnNEt3Cl (10 mol %) in DMSO at 100 °C (24 hours) gave the corresponding C-6 aminated products in excellent isolated yields (79–98%; ave. yield = 92%). These conditions worked well for simple unfunctionalized 1° alkylamines, 1° amines with methylene- or ethylene-linked aromatic or heteroaromatic functionality (e.g. benzene, thiophene, furan, indole, and pyridine), and 2° alkylamines such as pyrrolidine, morpholine, and piperidine were also well tolerated. The method is cost-effect, providing C-6 aminated products in consistently high yields, while at the same time utilizing far less toxic fluoride (10 fold less), than previous fluoride-promoted aminations. [ABSTRACT FROM AUTHOR]

An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP). [ABSTRACT FROM AUTHOR]

The possibility of stratifying patients according to differences in ROS proto‐oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well‐controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse‐transcription‐PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)‐1, ROS‐1, Ki67, and phosphorylated extracellular signal‐regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same. [ABSTRACT FROM AUTHOR]

Solid-phase peptide synthesis (SPPS) is the method of choice for the synthesis of peptides for research and production purposes. Despite having several positive features, it remains a challenge to reduce the amount of solvent waste generated during the synthesis. We proposed a 3-step protocol (in-situ Fmoc removal) where washing after coupling was eliminated. Here, the in-situ Fmoc removal protocol was optimized by adding an extra 4-methylpiperidine (4-MP) treatment to ensure the removal of the Fmoc. Additionally, a second addition of the carbodiimide during the coupling step is performed to form an in situ more active ester of the Fmoc-amino acid. The number of washings has been kept to a minimum of three adding in two of them 1% of OxymaPure to ensure the total removal of the 4-MP. This strategy, which saves up to 60% of solvent, was successfully demonstrated in two important Active Pharmaceutical Ingredients (APIs), angiotensin II and afamelanotide synthesis, with high purity. This strategy will be added to the green toolbox of SPPS making the approach more sustainable. [ABSTRACT FROM AUTHOR]

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities. [ABSTRACT FROM AUTHOR]

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with alane produced 1‐azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent‐free analogue with high activity. [ABSTRACT FROM AUTHOR]

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities. [ABSTRACT FROM AUTHOR]

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with alane produced 1‐azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent‐free analogue with high activity. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

The hybrid molecules were obtained by N-alkylation of piperidines, piperazines, tetrahydroisoquinoline, morpholine and phthalimide using N-chloroacetamide derivatives of 2,2,4-trimethyl-4-aryl-1,2,3,4-tetrahydroquinoline. The prepared compounds show moderate inhibitory activity in relation to the blood coagulation factor Xa. [ABSTRACT FROM AUTHOR]

The addition of diethylzinc to alk-2-yn-1-amines catalyzed by Cp2ZrCl2/EtMgBr resulted in regio- and stereoselective formation of (Z)-allk-2-en-1-amines in high yields. The presence of a morpholine or piperidine fragment in the initial propargylamine did not prevent the regio- and stereoselective addition. Carbocyclization of α,ω-bis(aminomethyl)alkadiynes was performed for the first time via Cp2ZrCl2/EtMgBr-catalyzed carbozincation with diethyl zinc. A probable mechanism of this reaction was proposed. [ABSTRACT FROM AUTHOR]

Treatment of the non-purified mixture of dinitro isomers obtained from the nitration of 1,4-dimethoxybenzene with piperidine led to the isolation of novel but minor adduct, 1-(2,5-dimethoxy-4-nitrophenyl)piperidine (2b) in 15% yield. Yields of nucleophilic aromatic substitution adducts are high when using purified 1,4-dimethoxy-2,5-dinitrobenzene (1b) with piperidine and pyrrolidine to give (2b) and 1-(2,5-dimethoxy-4-nitrophenyl)pyrrolidine (3b) in 76% and 82% yield, respectively. [ABSTRACT FROM AUTHOR]

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1. [ABSTRACT FROM AUTHOR]

[Display omitted] Anion exchange membrane fuel cells (AEMFCs), which are more economical than proton exchange membrane fuel cells (PEMFCs), stand out in the context of the rapid development of renewable energy. Superacid-catalyzed ether-free aromatic polymers have recently received a lot of attention due to their exceptional performance, but their development has been hampered by the trade-off between the dimensional stability and ionic conductivity of anion exchange membranes (AEMs). Here, we introduced fluoroketones containing different numbers of fluorinated groups (x = 0, 3 and 6) in the main chain of p-terphenyl piperidine because of the favorable hydrophobic properties of fluorinated groups. The results show that fluorinated AEMs can enhance OH− conductivity by building more aggregated hydrophilic channels while ensuring dimensional stability. The PTF6-QAPTP AEM with more fluorinated groups has the most excellent performance at 80 °C with an OH− conductivity of 142.7 mS cm−1 and a swelling ratio (SR) of only 4.55 %. Additionally, it exhibits good alkali durability, with the OH− conductivity and quaternary ammonium (QA) cation retaining at 93.45% and 92.6%, respectively, after immersion in a 2 M NaOH solution at 80 °C for 1200 h. In addition, the power density of the PTF6-QAPTP based single cell reaches 849 mW cm−2 when the current density is 1600 mA cm−2. The PTF6-QAPTP based cell has a voltage retention of 88% after 80 h of stability testing at a constant current density of 300 mA cm−2 at 80 °C. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed dearomative alkynylation of pyridines is reported with excellent regio‐ and enantioselectivities. The synthetically valuable enantioenriched 2‐alkynyl‐1,2‐dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three‐component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N‐ ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2‐addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non‐activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono‐alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed dearomative alkynylation of pyridines is reported with excellent regio‐ and enantioselectivities. The synthetically valuable enantioenriched 2‐alkynyl‐1,2‐dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three‐component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N‐ ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2‐addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non‐activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono‐alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported. [ABSTRACT FROM AUTHOR]