Preliminary Studies Research Articles

Numerical and experimental study of the conical connection of the blade of a rotary machine

The paper presents an experimental and numerical study of the tapered socket of the aluminum blade root of the mine main ventilation fan, which is based on the tests of a simplified full-scale model with a discarded airfoil and its subsequent finite element analysis. The calculation model takes into account elastoplastic properties of materials and non-linear contacts with friction. The proposed joint consists of an aluminum tapered blade root, two steel retainers with similar tapered surfaces, and two steel bolts that join the retainers around the root. Pre-tightening the bolts allows fixing the blade in an unloaded state in the socket and prevents its unwanted turns. Such a tightening is taken into account in the finite element analysis by means of determining, in compliance with special rules, the axial force of the pretension of the bolts. With the help of a hydraulic press acting on the lower surface of the airfoil root, the effect of the centrifugal load on the conical joint from the side of the blade airfoil is simulated. Nonlinear static analysis of the elastoplastic behavior of the structure allows determining the destructive loads that cause the bolts to break with the subsequent disconnection of the fasteners and the blade to fly out of the seat. The graphs of the equivalent von Mises stresses indicate that the maximum stresses are reached in the working part of the bolts, which fully corresponds to the nature of the destruction of the structure upon reaching the maximum equivalent load on it. The experimental study confirms the correctness of the determination of contact stresses at the tapered socket location. Correspondence of the results of the static analysis with the results of the full-scale experiment makes it possible to draw a conclusion about the correctness of the conducted finite element modelling. This allows using the developed formulation of the problem to determine the strength of rotor structures with conical connections of blades without performing preliminary experimental studies. In addition, the developed technique can be extended to a larger range of conical and cylindrical joints due to the simplicity of the approach and the versatility of the formulation of the nonlinear finite-element problem which models structures with preloaded or tensioned elements.

EFFECTS OF COMPANION ROBOTS ON DEPRESSION AND SOCIAL ISOLATION AMONG KOREAN AMERICAN OLDER ADULTS

Abstract Objectives During the COVID-19, older immigrants in low resource areas who are already excluded from much of social life, had to distance themselves even further, deepening their social isolation. Lack of stimulation can be particularly detrimental, as it influences mood and increases loneliness. Selected for cost-effectiveness and interactive features, we introduced the Companion Robot (CR) system. Preliminary studies conducted in South Korea found statistically significant improvement in quality of sleep and cognition among low-income older patients living alone with multiple chronic conditions and cognitive impairment. Method. Thirty CRs were deployed to solo-living Korean American older adults. We followed up with them after 3 months. In this Stage 1A clinical trial, we tested feasibility, usability and acceptability of CRs, investigating which features of CRs will help improve health behaviors such as medication adherence and daily exercises. Robotic Social Attitude (RoSAS) are assessed with a generic 18-items questionnaire (Krägeloh et al., 2019). Results The primary clinical outcomes measured at pre-and post-intervention were medication adherence and reduction of depression, social isolation and disabilities. The user-friendly doll-shaped design of CRs helped participants feel comfortable interacting with the CR on their own. Exposure to individualized CR-delivered content, including quizzes for brain training and inspirational messages, combined with consistent interaction with CR appeared to be beneficial for cognitive function. Discussion Since very few participants had reported diagnosis of dementia, we need to screen for undetected dementia using the Modified Mini-Mental Status Exam. The next stage is to implement further cultural adaptation for the U.S. participants.

PRO-HOME: AN IMPLEMENTATION SCIENCE FRAMEWORK FOR MULTILEVEL BARRIERS AND FACILITATORS IN LTSS

Abstract Promoting Seniors’ Health with Home Care Aides (Pro-Home) is a randomized controlled trial (RCT) of a gentle physical activity program for frail older adults conducted in a community-based long-term services and supports (LTSS) delivery setting. Pro-Home is a hybrid effectiveness-implementation study, which aims to examine (1) the effectiveness of the program delivered by home care aides (HCAs) in maintaining physical function in older homecare recipients, and (2) how the intervention works in a real-world Medicaid-funded LTSS system. This paper describes barriers and facilitators that have long existed or evolved during the Pro-Home development, using quantitative/qualitative data from the mixed-method study informed by an implementation science framework. Facilitators include the knowledge and partnerships that resulted from multiple preliminary studies that illuminated HCAs’ work/life-related stressors, coping resources, and underutilized capacity and motivation to promote the health of clients and HCAs themselves in the context of the LTSS system. Another facilitator has been the physical activity program developed in another state’s LTSS service setting (not in an academic setting). The program was easy to learn and adapt into a program to be delivered by HCAs (as opposed to care managers). Barriers included turbulent LTSS environments (e.g., rapidly growing managed care presence, COVID-19). Those barriers have been addressed through partnership with stakeholders at multiple levels. Having completed the intervention and data collection phases, we found the project’s planning and implementation challenging but rewarding. Pro-Home has produced rich information that will have many implications for research, practice, and LTSS services delivery and financing systems.

Einflussfaktoren auf die Patientenkompetenz und die Versorgung einsatzgeschädigter, psychisch erkrankter Soldat*innen der Bundeswehr: eine Interviewstudie mit Betroffenen

BackgroundThe number of service members of the German armed forces suffering from deployment-related mental health problems is steadily rising. Preliminary studies have shown that less than 50 % seek professional help. There is little knowledge about the factors influencing the development of an adequate level of patient competence to cope with the complexity of the clinical picture and the care of people with operational disabilities in the interprofessional network. MethodsThe article presents data gathered by semi-structured, guided interviews from 14 affected individuals analyzing salient beliefs about the perceived factors influencing their patient competence and care through the interprofessional network of supporters inside and outside the German armed forces. Data evaluation was carried out by means of content-structuring, qualitative content analysis using the method of deductive-inductive category formation. FindingsBased on the interviews conducted, we identified four groups of salient beliefs having an influence on patient competence: identify changes and limitations, recognize illness, redirect one’s life, help shape one‘s life again, and four groups of salient beliefs having an influence on care: intangible / material support, medical supplies, psychosocial support, third-party support. All main topics could be assigned to three levels of influence (individual, individual-contextual, contextual) and stored with a total of 70 topics (codes). InterpretationThe development of an effective “social structure” was named by those affected as an important influencing factor. Family members, comrades, superiors, and military GPs appear to have a significant impact on patient competence and care. The respondents' opinions about the importance of internal factors such as the soldier's self-image and fear of stigmatization are consistent with previous findings. Structural factors like supply procedures were mentioned as specific German armed forces phenomena.

Need Analysis for Development of a Role Playing Learning Model to Increase Student's Learning Motivation in Social Pathology Course

This study aims to (1) determine the needs of students regarding learning media that can help students improve learning outcomes and motivation; (2) the implementation of Social Pathology learning. It is research and development that is being done here. The Borg Gall development model—which includes preliminary and development studies, expert validation, model updates, hypothetical models derived from validation results, and model testing—is the one that is employed. According to Borg and Gall, the two primary goals of research and development procedures are product development and feasibility testing. Nevertheless, the scope of this research is restricted to the analytical phase, specifically examining the necessity of developing a role-playing learning model in social pathology courses to enhance the desire of students to learn. The participants in this research were third-semester social pathology students. 37 individuals made up the samples using the non-probability sampling method (saturated sample). A modified Likert scale was utilized to create the needs questionnaire, which had four response options: strongly agree, agree, disagree, and disagree strongly. Students and lecturers need a role-playing model. Students and lecturers in the Community Education Study Program need a role-playing model. This is demonstrated by the percentage that was found while examining the financial requirements of the student responses—90% of which were classified as strongly agreeing. Applying the role-playing learning paradigm can boost students' motivation and enhance their academic performance. This needs analysis can be used as the basis of learning innovations that will be applied to have an impact positive learning, which can improve learning motivation students significantly.

Successful initial restoration of oyster habitat in the lower Hudson River Estuary, United States

The eastern oyster (Crassostrea virginica), has experienced dramatic declines throughout its range, and most U.S. states along the Atlantic and Gulf of Mexico coasts have restoration programs. Oyster restoration in the Hudson River Estuary has been a focus of management agencies for over two decades. The present project was initiated in 2013 after sampling for replacement of the Tappan Zee bridge determined live oysters would be lost during bridge construction, thus requiring mitigation measures. Preliminary studies identified three areas for pilot studies to inform the design of full‐scale efforts. A pilot study involving deployment of oyster shell‐filled gabions and two styles of Reef Balls, found all substrates supported oyster recruitment and growth but there were higher oyster densities on gabions. Some of the gabions, however, failed structurally necessitating a need for new design. For full‐scale restoration, a total of 422 modified gabions and 881 Mini‐Bay style Reef Balls were deployed across three sites which totaled approximately 2.4 ha (6 ac) in seafloor area. Both substrate types were heavily colonized by oysters and several other species at all three sites, essentially duplicating the findings of the pilot study. The final monitoring event in 2020 indicated a total of approximately 5.8 million live oysters were on the substrates deployed in 2018. This mitigation effort was the largest oyster habitat restoration project in, or north of, the New York Harbor region in recent decades based on restoration area and several oyster metrics of early success.

A combined catalytic and kinetic study of the aqueous-biphasic hydrogenation of allylbenzenes by using a dihydride-ruthenium complex containing tri(sodium-o-sulfonatedphenylphosphine) ligands

The water-soluble complex Ru(H)2(CO)(o-TPPTS)3 was used as a catalyst precursor for the hydrogenation of naturally occurring allylbenzenes, such as eugenol, estragole, and safrole, in an aqueous biphasic system. Under the best-operating conditions, P = 900 psi (62 atm), Tθ = 90 °C (363.15 K), S/C ratio = 80/1, time = 6 h, and stirring rate = 800 rpm, this catalyst precursor showed a good activity and selectivity towards C = C bond hydrogenation. When working with eugenol, the isomerization by-product (isoeugenol) was obtained in addition to the hydrogenation product. Preliminary kinetics studies indicate that the individual reactivity order was estragole > allylbenzene > safrole > eugenol. In contrast, a quaternary olefin mixture showed that the hydrogenation rate was somewhat similar to that of individual allylbenzene. The classic Hg test confirmed the molecular nature of the Ru water-soluble complex. Finally, the catalyst recycling study indicates that this complex can be used up to three times, maintaining the same catalytic activity.

Functional capabilities of ceramic nanostructures used for reinforcement of polymer structural materials for dental purposes

Objective. To present biomechanical substantiation of the possibility of using a post-resection obturator prosthesis made of polyamide thermoinjection material, dispersion-reinforced with nanostructured titanium dioxide.
 Materials and methods. The biomechanical method of mathematical modeling was applied in the work. The construction of the calculated finite element model included: determination of the mechanical properties of materials; construction of a geometric model; creation of a finite element grid; setting the boundary conditions of force effects.
 Results. Preliminary studies of the physical and mechanical characteristics of reinforced polyamide showed an increase in maximum stresses and Ung's modulus by 8,4 % and 7,2 %, respectively, which corresponds to the standards of ISO 1567: 1999. The results of biomechanical calculations of the strength of the elements of the prosthesis-obturator are the following: the level of maximum stresses within the strength indicators under horizontal load is 45,25 MPa, under vertical load (equivalent stress value) – 30,88 MPa, maximum stresses in the contact area with the occlusal pad – 35,00 MPa, deformations determined in the load area – 0,001, and the presence of retaining clasps distributes stresses on the surface of the supporting tooth and reduces them by 11 %. These facts determine a sufficient stability and good fixation of the post-resection prosthesis.
 Conclusions. Based on the results of physical and mechanical studies of the maxillary prosthesis-obturator made of thermo-injection polyamide reinforced with nanoscale titanium dioxide, the necessary strength characteristics and structures were determined, that indicates the prospects for its clinical application in the practice of an orthopedic dentist for the treatment of patients with acquired defects of the jaw bones.

Investigating Lycotoxin-An1a (An1a), a defense antiviral peptide from Alopecosa nagpag venom as prospective anti-dengue agent against DENV-2 NS2B-NS3 protease

Dengue fever is a global health concern with no effective therapy. Screening synthetic chemicals, animal-originated compounds, and phytocompounds against Dengue virus (DENV) targets has failed to find dengue antivirals. The current study examines animal drugs as antagonists against NS2B-NS3Pro, one of DENV's most promising therapeutic targets for dengue fever. Antiviral-Lycotoxin-An1a (An1a), a defence antiviral peptide isolated from the venom of Alopecosa nagpag, a toxic spider. Based on prior in vitro research, it was discovered that the venom peptide suppresses the action of DENV-2 NS2B-NS3Pro. An1a peptide with NS2B-NS3Pro wild type (WT) and two mutants (H51N and S135A) was tested for anti-dengue characteristics using in silico analysis. The WT NS2B-NS3Pro has a catalytic triad of His51, Asp75, and Ser135 in the active site, but the mutants have N51 instead of His51 and Ala135 instead of Ser135. The dynamic sites of the three proteases (WT, H51N, S135A) and the peptide toxin (An1a) were taken into account to achieve molecular docking of An1a with WT NS2B-NS3Pro in conjunction with H51N and S135A. Cluspro-2 performs rigid-flexible docking to predict peptide binding affinity, effectiveness, and inhibitory consistency. Since the ligand had a higher binding affinity, docking score, and molecular interaction network, MD simulations and MM-GBSA free energy calculations were used to investigate the stability of the three protein-peptide complexes. The computer-aided screening and manufacture of spider venom-based anti-dengue medicines yielded intriguing results in the preliminary studies. This study is significant in defining the ideal therapeutic candidate against dengue infections.

Analysis and evaluation of prospects for high-quality quartz resources in the North Caucasus

Quartz resources play a crucial role in the development of key economic sectors, particularly in the production of chemically pure silicon. The extraction and processing of these resources necessitate high-tech methods to obtain the desired silicon output. Presently, the demand for silicon stands at 5–6 Ktpa, while the supply remains at 2300 t. An analysis of the chemical properties of various rocks (quartzites, quartz sands, vein quartz) in the Republic of North Ossetia–Alania reveals that their parametric characteristics align with the requirements for silicon production. The researchers in North Ossetia have successfully grown singlecrystal silicon and produced photovoltaic converters. Russian scientists have also achieved the first melting of metallurgical silicon into polycrystalline silicon using vacuum furnaces and electron-beam remelting, yielding promising results. The goal of this research is to analyze and assess the potential of high-quality quartz resources in the North Caucasus. The main objectives include identifying sites with optimal quartz deposits suitable for silicon production, conducting localization, estimating forecast resources, and designating areas for further investigation. The selected sites are expected to possess advantageous geographical and economic features, along with favorable mining conditions conducive to open-pit mining.The study focuses on the Fiagdon site in the Alagir District, RNO-Alania. Various methods, including laboratory work, sampling, examination of constructed sections, and a comprehensive review of mine workings and borehole documentation, were employed. Conclusions from mineralogical and petrographic analyses, alongside laboratory studies and process tests, contributed to the research methodology. The results of the research encompassed the analysis of statistical, economic, geological, and process-related information necessary for addressing primary geological objectives. Subsequent steps involved the selection of prospects for further exploration, specification of geological maps at a 1:10000 scale with accompanying legends and sections, determination of the conditions, morphology, and parameters of productive deposits, and preliminary studies on the quality and process characteristics of quartz resources. Furthermore, the P2 forecast resources of high-quality quartz raw materials for silicon production were localized, estimated at 500 Kt, and rigorously tested. The study’s discoveries have led to the formulation of recommendations for future exploration endeavors.

The Therapeutic Potential of Cannabidiol in Revolutionising Opioid Use Disorder Management.

Opioid use disorder (OUD) is a significant cause of morbidity and mortality worldwide and is linked to a complex interplay of biopsychosocial factors as well as the increasing overprescription and availability of opioid medications. Current OUD management relies on the controlled provision of opioid medications, such as methadone or buprenorphine, known as opioid replacement therapy. There is variable evidence regarding the long-term efficacy of these medications in improving the management of OUD, thereby necessitating an exploration into innovative approaches to complement, or even take the place of, existing treatment paradigms. Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has garnered attention for its diverse pharmacological properties, including anti-inflammatory, analgesic, and anxiolytic effects. Preliminary studies suggest that CBD may target opioid withdrawal pathways that make CBD a potential therapeutic option for OUD. This narrative review synthesises current literature surrounding OUD and offers a nuanced review of the current and future role of CBD in managing this condition.In doing so, we highlight the potential avenues to explore with respect to CBD research for the guidance and development of further research opportunities, framework and policy development, and clinical considerations before medicinal CBD can be integrated into evidence-based clinical guidelines.

Effect of experimental therapy on the gas and acid–base composition of the blood in the dynamics of toxic pulmonary edema

BACKGROUND: This study is part of an extended research onfinding ways to prevent and treat toxic pulmonary edema. This study aimed to examine the gas transport function, acid–base state, and gas composition of blood in the dynamics of experimental toxic pulmonary edema and the effect on them of experimental therapy with a combination of drugs that have shown effectiveness in preliminary studies.
 MATERIALS AND METHODS: Toxic edema of the lungs was modeled in mice by inhalation of toxic doses of phosgene LСt50. Gas and acid–base composition parameters of the blood were determined using a gas analyzer 3 and 24 h after poisoning. Thirty minutes after poisoning, parts of the animals were injected intraperitoneally with a complex of drugs consisting of natrii dimercaptopropansulfonas (unitiol) 150 mg/kg, diclofenac sodium 35. 0 mg/kg, and аprotinin (contrikal) 250 IU/kg.
 RESULTS: The results revealed 3 h after poisoning of animals, changes in the gas composition and parameters of the gas transport function in the blood were detected, and 24 h after poisoning, impaired acid-base balance was noted. The use of a therapeutic combination of drugs consisting of sodium dimercaptopropanesulfonate (unithiol), sodium diclofenac, and aprotinin (kontrikal) led to the partial normalization of the altered parameters of the blood gas composition and parameters of the blood gas transport function but was not accompanied by the normalization of the acid-base state of the blood. The formulation demonstrated a pronounced negative effect on the blood gas composition in intact animals. The treatment of pulmonary edema with the comparison drug unithiol did not result in the normalization of the gas composition and acid-base state of the poisoned animals.
 CONCLUSION:The treatment of toxic pulmonary edema with a combination of medications led to an improvement in the gas composition and gas transport function of the blood.

Pd(OAc)2/Xantphos Catalyzed Reductive Coupling of Sulfonyl Chlorides: Synthesis of Thioethers by Sulphur Dioxide Extrusion

AbstractHerein, we reported a successful cross coupling of aryl sulfonyl chlorides to forge thioether skeleton via Pd catalysis. This transformation proceeded in the presence of Xantphos. Preliminary mechanism studies demonstrated dual roles of Xantphos: (i) a reductant that reduced sulfonyl radical to thio radical; (ii) a ligand that promotes coupling reactions.

Temporal and spatial variation in the food web structure in artificial reef areas and adjacent habitats in Haizhou Bay

Artificial reef is regarded as an effective tool for restoring habitats and supporting the marine ecosystem. While the energy flow and material exchange in the food web of artificial reef ecosystem still remain vacant and should be further understood. In this study, stable isotopic characteristics (δ13C and δ15N) were used to identify the trophic niches and potential carbon sources of consumers (fish and invertebrates) in artificial reef areas and adjacent habitats in Haizhou Bay (the estuary area (EA), the aquaculture area (AA), the artificial reef area (AR), the natural area (NA) and the comprehensive effect area (CEA)) in spring and autumn. The results showed that the average δ13C for all consumers decreased from − 16.99 ± 2.07‰ to − 21.81 ± 1.66‰, and the average δ15N ranged from 11.37 ± 0.35‰ to 14.69 ± 0.64‰ in all seasons. A SIBER model revealed highly similar trophic niche among habitats in autumn, and lower overlap in spring. The SIMMR model showed that phytoplankton and sedimentary organic matter (SOM) were the major contributors to consumers, and particulate organic matter (POM) accounted for less contribution. In AA and NA phytoplankton and SOM generally contributed fairly equally to most fish, while single SOM sources were major contributors to nearly all the species in AR and CEA. Our findings reveal that ARs can serve as seascape mosaics to increase fish community diversity because of their high variation in the δ13C value and the trophic niches from EA to the NA. Preliminary multidisciplinary studies are needed for the mitigation of effects before any implementations deployed to the offshore waters that influence habitat connectivity, especially some habitat–specific migratory species.

Analysis of the management and therapeutic performance of diabetes mellitus employing special target.

Diabetes mellitus (DM) is a chronic metabolic condition characterized predominantly by hyperglycemia. The most common causes contributing to the pathophysiology of diabetes are insufficient insulin secretion, resistance to insulin's tissue-acting effects, or a combination of both. Over the last 30 years, the global prevalence of diabetes increased from 4% to 6.4%. If no better treatment or cure is found, this amount might climb to 430 million in the coming years. The major factors of the disease's deterioration include age, obesity, and a sedentary lifestyle. Finding new therapies to manage diabetes safely and effectively without jeopardizing patient compliance has always been essential. Among the medications available to manage DM on this journey are glucagon-like peptide-1 agonists, thiazolidinediones, sulphonyl urease, glinides, biguanides, and insulin-targeting receptors discovered more than 10 years ago. Despite the extensive preliminary studies, a few clinical observations suggest this process is still in its early stages. The present review focuses on targets that contribute to insulin regulation and may be employed as targets in treating diabetes since they may be more efficient and secure than current and traditional treatments.

Spelling Bee as an Effective Strategy for Vocabulary Learning among Pre-NCE Students

This paper intends to investigate the effectiveness of the Spelling Bee Approach (SBP) on vocabulary learning. Thus, Kano State College of Education and Preliminary Studies (KASCEPS) students were used to ascertain whether the approach is effective. Therefore, the population included all Pre-NCE students in the Department of English and European Languages, specifically in the second semester of the 2020/2021 Academic Session. To this end, a systematic random sampling method was utilized in taking the sample size. There were 18 students as the sample size obtained from the total number of 42 students’ population offering English along with other combinations. Furthermore, the paper adopted an experimental design, particularly a pre-test and post-test control group design. The Spelling Dictation Achievement Test (SDAT) was employed as the instrument of the data collection. The 18 students of the sample size constituted both experimental and control groups of the study. The data was analysed using a t-test for independent samples. The result indicated a mean of 70.33 for the experimental group and 30.22 for the control group. Given that, a deduction can be made that Spelling Bee Approach is effective in vocabulary learning. Hence, teachers/lecturers can employ it to teach vocabulary development.

CHKB-AS1 enhances proliferation and resistance to NVP-BEZ235 of renal cancer cells via regulating the phosphorylation of MAP4 and PI3K/AKT/mTOR signaling

Targeted therapy is pivotal in renal carcinoma treatment, and the dual-inhibitor NVP-BEZ235 has emerged as a promising candidate in preliminary studies. Its effectiveness against renal carcinoma and the mechanisms underlying potential resistance, however, warrant further exploration. This study aims to elucidate these aspects, enhancing our understanding of NVP-BEZ235's future clinical utility. To investigate resistance mechanisms, renal cancer cell lines were exposed to progressively increasing concentrations of NVP-BEZ235, leading to the development of stable resistance. These resistant cells underwent extensive RNA-sequencing analysis. We implemented gene interference techniques using plasmid vectors and lentivirus and conducted regular IC50 assessments. To pinpoint the role of LncRNAs, we utilized FISH and immunofluorescence staining assays, supplemented by RNA pull-down and RIP assays to delineate interactions between LncRNA and its RNA-binding protein (RBP). Further, Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway. This interaction contributes to a diminished antitumor effect of NVP-BEZ235, highlighting the intricate mechanism through which CHKB-AS1 modulates drug resistance pathways, potentially impacting therapeutic strategies against renal carcinoma.

Electroreductive hydroxy fluorosulfonylation of alkenes

An electroreductive strategy for radical hydroxyl fluorosulfonylation of alkenes with sulfuryl chlorofluoride and molecular oxygen from air is described. This mild protocol displays excellent functional group compatibility, broad scope, and good scalability, providing convenient access to diverse β-hydroxy sulfonyl fluorides. These β-hydroxy sulfonyl fluoride products can be further converted to valuable aliphatic sulfonyl fluorides, β-keto sulfonyl fluorides, and β-alkenyl sulfonyl fluorides. Further, some of these products showed excellent inhibitory activity against Botrytis cinerea or Bursaphelenchus xylophilus, which could be useful for potent agrochemical discovery. Preliminary mechanistic studies indicate that this transformation is achieved through rapid O2 interception by the alkyl radical and subsequent reduction of the peroxy radical, which outcompete other side reactions such as chlorine atom transfer, hydrogen atom transfer, and Russell fragmentation.

Photoredox-Catalyzed Tandem Cyclization of Enaminones with N-Sulfonylaminopyridinium Salts toward the Synthesis of 3-Sulfonaminated Chromones.

A photoredox-catalyzed intermolecular tandem sulfonamination/cyclization of enaminones was realized by using N-aminopyridinium salts as the sulfonaminated reagents without transition-metal catalysts or bases. The reaction exhibits a broad scope and good functional group tolerance, good yields, and regioselectivity. Preliminary mechanistic studies support the radical property of the reaction and the involvement of N-centered radical intermediates.

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.