Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity.

YesDual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity

Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia

Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia : The SAFEHEART study

Funding: This study was supported by Fundación Hipercolesterolemia Familiar; Grant G03/181 Grant 08-2008 Centro Nacional de Investigaci?n Cardiovascular (CNIC).Background: Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH. Objectives: The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk. Methods: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. Results: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5-10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67-3.39) and 1.22 (0.54-2.93) at enrollment for ATV and RV, respectively (P <.001). There were no significant differences at the follow-up: 1.29 (0.54-2.82) and 1.22 (0.54-2.76) in the ATV and RV groups, respectively (P =.51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P =.58). Conclusion: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated

Active and durable R2MnRuO7 pyrochlores with low Ru content for acidic oxygen evolution

The production of green hydrogen in water electrolyzers is limited by the oxygen evolution reaction (OER). State-of-the-art electrocatalysts are based on Ir. Ru electrocatalysts are a suitable alternative provided their performance is improved. Here we show that low-Ru-content pyrochlores (R2MnRuO7, R = Y, Tb and Dy) display high activity and durability for the OER in acidic media. Y2MnRuO7 is the most stable catalyst, displaying 1.5 V at 10 mA cm−2 for 40 h, or 5000 cycles up to 1.7 V. Computational and experimental results show that the high performance is owed to Ru sites embedded in RuMnOx surface layers. A water electrolyser with Y2MnRuO7 (with only 0.2 mgRu cm−2) reaches 1 A cm−2 at 1.75 V, remaining stable at 200 mA cm−2 for more than 24 h. These results encourage further investigation on Ru catalysts in which a partial replacement of Ru by inexpensive cations can enhance the OER performance. © 2023, The Author(s).We acknowledge the funding granted to the PROMET-H2 project by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 862253. The Deputyship for Research & Innovation, Ministry of Education of Saudi Arabia is acknowledged for funding this research work through project number 341. Financial support from grants PID2019−103967RJ-I00, PID2020-116712RB-C21, and PID2021-122477OB-I00 funded by MCIN/AEI/10.13039/501100011033 is acknowledged. The authors acknowledge Diamond Light Source for time on Beamline B18 and ALBA synchrotron for beamtime at MSPD line. The authors wish to acknowledge the Deutsche Akademische Austausch Dienst (DAAD), Scholarship code number 57540124. F.C.V. and M.J.K. acknowledge that the grants RTI2018-095460-B-I00, RYC-2015-18996, and MDM-2017-0767 were funded by MCIN/AEI/ 10.13039/501100011033 and by the European Union. The use of supercomputing facilities at SURFsara was sponsored by NWO Physical Sciences, with financial support from NWO.Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-023-37665-9.Peer reviewe

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration

Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes–2

[No abstract available][Not available

Insights into the High Activity of Ruthenium Phosphide for the Production of Hydrogen in Proton Exchange Membrane Water Electrolyzers

The demand of green hydrogen, that is, the hydrogen produced from water electrolysis, is expected to increase dramatically in the coming years. State-of-the-art proton exchange membrane water electrolysis (PEMWE) uses high loadings of platinum group metals, such as Pt in the electrode where hydrogen is produced. Alternative electrodes based on phosphides, sulfides, nitrides, and other low-cost alternatives are under investigation. Herein, a simple process for the preparation of RuP electrodes with high activity for the hydrogen evolution reaction (HER) in acidic electrolyte is described. A straightforward one-pot synthesis that yields RuP nanoparticles with fine-tuned composition and stoichiometry is presented, as determined by multiple characterization techniques, including lab- and synchrotron-based experiments and theoretical modeling. The RuP nanoparticles exhibit a high activity of 10 mA cm−2 at 36 mV overpotential and a Tafel slope of 30 mV dec−1, which is comparable to Pt/C. Moreover, a RuP catalyst-coated membrane (CCM) with a low Ru loading of 0.6 mgRu cm−2 is produced and tested in a PEMWE cell configuration, yielding 1.7 A cm−2 at 2 V. © 2023 The Authors. Advanced Energy and Sustainability Research published by Wiley-VCH GmbH.The authors acknowledge the PROMET-H2 project. This project received funding from the European Union Horizon 2020 research and innovation programme under grant agreement no. 862253. The Deputyship for Research & Innovation, Ministry of Education of Saudi Arabia, is acknowl edged for funding this research work through the project number 341. The authors also acknowledge financial support from grants TED2021- 131033B-I00, PID2020-116712RB-C21, and PID2019-103967RJ-I00 funded by MCIN/AEI/10.13039/501100011033. Computing resources for this work were provided by STFC scientific computing departments of the SCARF cluster. J.T. wishes to acknowledge the Deutsche Akademische Austausch Dienst (DAAD), scholarship code number 57540124. The authors acknowledge Diamond Light Source for time on the VerSoX B07-B beamline under the commissioning proposal cm-28150Peer reviewe

Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer’s disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments—huprine and rhein— that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8–14, 154–169 and 307–318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable “floppy” pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with &gt;80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Evaluation of cryptolepine and huperzine derivatives as lead compounds towards new agents for the treatment of human African Trypanosomiasis.

noThe alkaloid cryptolepine (1) and eight synthetic analogues (2-8) were assessed for in vitro activities against Trypanosoma brucei. Four of the analogues were found to be highly potent with IC50 values of less than 3 nM and three of these were assessed against T. brucei brucei infection in rats. The most effective compound was 2,7-dibromocryptolepine (7); a single oral dose of 20 mg/Kg suppressed parasitaemia and increased the mean survival time to 13.6 days compared with 8.4 days for untreated controls. In addition, four huperzine derivatives (9-12) were shown to have in vitro antitrypanosomal activities with IC50 values from 303-377 nM