The long wait for long-acting HIV prevention and treatment formulations.

Large randomised studies of new long-acting medications for the prevention and treatment of HIV have shown high effectiveness and acceptability. Although modelling studies indicate these agents could be fundamental in HIV elimination, coordination of their entry into health-care markets is crucial, especially in low-income and middle-income countries with high HIV prevalence, where coordination is low despite UNAIDS flagging that global HIV targets will not be met. Research and implementation projects are tightly controlled by originator pharmaceutical companies, with only a small percentage of eligible people living with or affected by HIV benefiting from these projects. WHO, financial donors, manufacturers, and governments need to consider urgent coordinated action from stakeholders worldwide, akin to the successful introduction of dolutegravir into treatment programmes across low-income and middle-income countries. Without this immediate coordination, large-scale access to long-acting agents for HIV will be delayed, potentially extending into the 2030s. This delay is unacceptable considering the established global HIV targets.

Boron Nanoparticle-Enhanced Proton Therapy: Molecular Mechanisms of Tumor Cell Sensitization.

Boron-enhanced proton therapy has recently appeared as a promising approach to increase the efficiency of proton therapy on tumor cells, and this modality can further be improved by the use of boron nanoparticles (B NPs) as local sensitizers to achieve enhanced and targeted therapeutic outcomes. However, the mechanisms of tumor cell elimination under boron-enhanced proton therapy still require clarification. Here, we explore possible molecular mechanisms responsible for the enhancement of therapeutic outcomes under boron NP-enhanced proton therapy. Spherical B NPs with a mode size of 25 nm were prepared by methods of pulsed laser ablation in water, followed by their coating by polyethylene glycol to improve their colloidal stability in buffers. Then, we assessed the efficiency of B NPs as sensitizers of cancer cell killing under irradiation with a 160.5 MeV proton beam. Our experiments showed that the combined effect of B NPs and proton irradiation induces an increased level of superoxide anion radical generation, which leads to the depolarization of mitochondria, a drop in their membrane mitochondrial potential, and the development of apoptosis. A comprehensive gene expression analysis (via RT-PCR) confirmed increased overexpression of 52 genes (out of 87 studied) involved in the cell redox status and oxidative stress, compared to 12 genes in the cells irradiated without B NPs. Other possible mechanisms responsible for the B NPs-induced radiosensitizing effect, including one related to the generation of alpha particles, are discussed. The obtained results give a better insight into the processes involved in the boron-induced enhancement of proton therapy and enable one to optimize parameters of proton therapy in order to maximize therapeutic outcomes.

Muscle degeneration in aging Drosophila flies: the role of mechanical stress.

Muscle wasting is a universal hallmark of aging which is displayed by a wide range of organisms, although the causes and mechanisms of this phenomenon are not fully understood. We used Drosophila to characterize the phenomenon of spontaneous muscle fiber degeneration (SMFD) during aging. We found that SMFD occurs across diverse types of somatic muscles, progresses with chronological age, and positively correlates with functional muscle decline. Data from vital dyes and morphological markers imply that degenerative fibers most likely die by necrosis. Mechanistically, SMFD is driven by the damage resulting from muscle contractions, and the nervous system may play a significant role in this process. Our quantitative model of SMFD assessment can be useful in identifying and validating novel genetic factors that influence aging-related muscle wasting.

Connecting Female Entertainment Workers in Cambodia to Health Care Services Using mHealth: Economic Evaluation of Mobile Link.

BACKGROUND: Mobile Link is a mobile phone-based intervention to increase access to, and use of, health care services among female entertainment workers in Cambodia who face higher risks for specific diseases and gender-based violence. A multisite randomized controlled trial showed that Mobile Link connected female entertainment workers with outreach workers for information and escorted referrals after 6 months but did not lead to statistically significant improvements in HIV and sexually transmitted infection testing, contraceptive use, and condom use. OBJECTIVE: This study aims to conduct a 3-part economic evaluation of Mobile Link to understand its costs, value, and affordability. METHODS: We conducted cost, cost-effectiveness, and budget impact analyses of Mobile Link using cost and outcomes data from the Mobile Link trial and other sources. For the cost analysis, we estimated the total, per-person, and incremental costs of Mobile Link compared with usual care. Using probabilistic decision-analytic models, we estimated the 1-year cost-effectiveness of Mobile Link from payer and combined payer and patient perspectives by converting selected primary and secondary outcomes from the trial to disability-adjusted life years (DALYs) averted. Finally, we estimated the financial costs of scaling up Mobile Link's messaging and outreach services to 70% of female entertainment workers in 5 years. RESULTS: The incremental costs of Mobile Link were US $199 from a payer perspective and US $195 per person from a combined payer and patient perspective. With an average of 0.018 (95% predicted interval -0.088 to 0.126) DALYs averted, Mobile Link's cost-effectiveness was US $10,955 per DALY from a payer perspective (US $10,755 per DALY averted from a payer and patient perspective). The costs of Mobile Link would have to decrease by 85%, or its effectiveness would have to be 5.56 times higher, for the intervention to meet the upper limit of recommended cost-effectiveness thresholds in Cambodia (US $1671 per DALY averted). The 5-year cost of scaling Mobile Link to 34,790 female entertainment workers was estimated at US $1.64 million or US $46 per person per year. CONCLUSIONS: This study provided a comprehensive economic evaluation of Mobile Link. We found that Mobile Link is not likely to be cost-effective unless its costs decrease or its effectiveness increases. Scaling up Mobile Link to more female entertainment workers is estimated to cost less than the costs of the trial. Given the importance of linking female entertainment workers to essential services, future research should focus on enhancing the effectiveness of Mobile Link or developing new mobile health interventions for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03117842; https://clinicaltrials.gov/study/NCT03117842.

Solid-State Synthesis of Na4Fe3(PO4)2P2O7/C by Ti-Doping with Promoted Structural Reversibility for Long-Cycling Sodium-Ion Batteries.

The cathode material Na4Fe3(PO4)2P2O7 (NFPP) has shown great potential for sodium-ion batteries (SIBs) due to its cost-effectiveness, prolonged cycle life, and high theoretical capacity. However, the practical large-scale production of NFPP is hindered by its poor intrinsic electron conductivity and the presence of a NaFePO4 impurity. In this study, we propose a mutually reinforcing approach involving Ti doping, mechanical nano treatment, and in situ carbon coating to produce Ti-NFPP via the solid-state methods of synthesis. Ti doping strengthens the covalent Fe-O interaction, hence accelerating the electron transfer and the redox reactions Fe2+/Fe3+. In situ carbon coating improves electrical conductivity and allows for accommodating the volumetric variation. Nanosized treatment promotes the uniform progression of solid-state reactions. The synthesized Na4Fe2.98Ti0.01(PO4)2P2O7 material (Ti-NFPP) exhibits promising electrochemical properties with an initial discharge specific capacity of 112.5 mA h g-1 at 0.1 C. A volumetric change of only 2.98% was observed during the de/sodiation process, indicating an enhanced reversibility of the crystal lattice. Moreover, it demonstrates exceptional cycling stability with a capacity retention rate of 97.2 mA h g-1 at 10 C over 5000 cycles. These findings offer a promising pathway for the large-scale production of Ti-NFPP in SIBs.

Dynamic modulation of the processing of unpredicted technical errors by the posterior cingulate and the default mode network.

The pervasive use of information technologies (IT) has tremendously benefited our daily lives. However, unpredicted technical breakdowns and errors can lead to the experience of stress, which has been termed technostress. It remains poorly understood how people dynamically respond to unpredicted system runtime errors occurring while interacting with the IT systems on a behavioral and neuronal level. To elucidate the mechanisms underlying such processes, we conducted a functional magnetic resonance imaging (fMRI) study in which 15 young adults solved arithmetic problems of three difficulty levels (easy, medium and hard) while two types of system runtime errors (problem errors and feedback errors) occurred in an unexpected manner. The problem error condition consisted of apparently defective displays of the arithmetic problem and the feedback error condition involved erroneous feedback. We found that the problem errors positively influenced participants' problem-solving performance at the high difficulty level (i.e., hard tasks) at the initial stage of the session, while feedback errors disturbed their performance. These dynamic behavioral changes are mainly associated with brain activation changes in the posterior cingulate and the default mode network, including the posterior cingulate cortex, the mPFC, the retrosplenial cortex and the parahippocampal gyrus. Our study illustrates the regulatory role of the posterior cingulate in coping with unpredicted errors as well as with dynamic changes in the environment.

Gadolinium Doping Modulates the Enzyme-like Activity and Radical-Scavenging Properties of CeO2 Nanoparticles.

Their unique physicochemical properties and multi-enzymatic activity make CeO2 nanoparticles (CeO2 NPs) the most promising active component of the next generation of theranostic drugs. When doped with gadolinium ions, CeO2 NPs constitute a new type of contrast agent for magnetic resonance imaging, possessing improved biocatalytic properties and a high level of biocompatibility. The present study is focused on an in-depth analysis of the enzyme-like properties of gadolinium-doped CeO2 NPs (CeO2:Gd NPs) and their antioxidant activity against superoxide anion radicals, hydrogen peroxide, and alkylperoxyl radicals. Using an anion-exchange method, CeO2:Gd NPs (~5 nm) with various Gd-doping levels (10 mol.% or 20 mol.%) were synthesized. The radical-scavenging properties and biomimetic activities (namely SOD- and peroxidase-like activities) of CeO2:Gd NPs were assessed using a chemiluminescent method with selective chemical probes: luminol, lucigenin, and L-012 (a highly sensitive luminol analogue). In particular, gadolinium doping has been shown to enhance the radical-scavenging properties of CeO2 NPs. Unexpectedly, both bare CeO2 NPs and CeO2:Gd NPs did not exhibit SOD-like activity, acting as pro-oxidants and contributing to the generation of reactive oxygen species. Gadolinium doping caused an increase in the pro-oxidant properties of nanoscale CeO2. At the same time, CeO2:Gd NPs did not significantly inhibit the intrinsic activity of the natural enzyme superoxide dismutase, and CeO2:Gd NPs conjugated with SOD demonstrated SOD-like activity. In contrast to SOD-like properties, peroxidase-like activity was observed for both bare CeO2 NPs and CeO2:Gd NPs. This type of enzyme-like activity was found to be pH-dependent. In a neutral medium (pH = 7.4), nanoscale CeO2 acted as a prooxidant enzyme (peroxidase), while in an alkaline medium (pH = 8.6), it lost its catalytic properties; thus, it cannot be regarded as a nanozyme. Both gadolinium doping and conjugation with a natural enzyme were shown to modulate the interaction of CeO2 NPs with the key components of redox homeostasis.

Preferences in Clinical Care of Individuals With Differences of Sex Development.

OBJECTIVES: To identify the most important attributes related to the process of achieving, and outcomes associated with, successful care for differences of sex development (DSD). METHODS: We developed a best-worst scaling survey administered to 520 DSD stakeholders, including individuals or family members of those with DSD, health care specialists, and patient support and advocacy representatives. Fourteen process-related attributes and 16 outcome-related attributes were identified through qualitative research. We estimated relative importance scores and coefficients from regression analysis to understand the relative importance of attributes and conducted latent class analysis to explore heterogeneity in preferences. RESULTS: The 3 most important process attributes were (1) good communication between care team and patient/family, (2) care team educated patient/family about condition, and (3) care team incorporates the values of patient/family. The 3 most important outcome attributes were (1) patient satisfaction, (2) patient mental health, and (3) treatment maintains physical health. Latent class analyses showed that respondents had heterogeneous preferences. For process-related attributes, we identified 3 respondent groups: "Patient autonomy and support" (46% of respondents), "Education and care transitions" (18%), and "Shared decision-making" (36%). For outcome-related attributes, we identified 2 respondent groups: "Preserving function and appearance" (59% of respondents) and "Patient health and satisfaction" (41%). CONCLUSIONS: Outcomes such as patient satisfaction and health were the most important outcome attributes, and good communication and education from the care team were the most important process attributes. Respondents expressed heterogeneous preferences for selected DSD care attributes that providers should consider to improve satisfaction with and quality of DSD care.

Orthopedic postoperative infection profile and antibiotic sensitivity of 2038 patients across 24 countries - Call for region and institution specific surgical antimicrobial prophylaxis.

Purpose: Improper utilization of surgical antimicrobial prophylaxis frequently leads to increased risks of morbidity and mortality.This study aims to understand the common causative organism of postoperative orthopedic infection and document the surgical antimicrobial prophylaxis protocol across various institutions in to order to strengthen surgical antimicrobial prophylaxis practice and provide higher-quality surgical care. Methods: This multicentric multinational retrospective study, includes 24 countries from five different regions (Asia Pacific, South Eastern Africa, Western Africa, Latin America, and Middle East). Patients who developed orthopedic surgical site infection between January 2021 and December 2022 were included. Demographic details, bacterial profile of surgical site infection, and antibiotic sensitivity pattern were documented. Results: 2038 patients from 24 countries were included. Among them 69.7 % were male patients and 64.1 % were between 20 and 60 years. 70.3 % patients underwent trauma surgery and instrumentation was used in 93.5 %. Ceftriaxone was the most common preferred in 53.4 %. Early SSI was seen in 55.2 % and deep SSI in 59.7 %. Western Africa (76 %) and Asia-Pacific (52.8 %) reported a higher number of gram-negative infections whereas gram-positive organisms were predominant in other regions. Most common gram positive organism was Staphylococcus aureus (35 %) and gram-negative was Klebsiella (17.2 %). Majority of the organisms showed variable sensitivity to broad-spectrum antibiotics. Conclusion: Our study strongly proves that every institution has to analyse their surgical site infection microbiological profile and antibiotic sensitivity of the organisms and plan their surgical antimicrobial prophylaxis accordingly. This will help to decrease the rate of surgical site infection, prevent the emergence of multidrug resistance and reduce the economic burden of treatment.

Association Between Alcohol Use Disorder and Hospital Readmission Rates and Outcomes in Cancer Survivors: A Population Cohort Study.

BACKGROUND: Alcohol use disorder (AUD) is the most common substance use disorder and is characterized by heavy alcohol use and the inability to control drinking. This study sought to compare the rate, timing, length, and total costs of hospital readmissions among cancer survivors with and without AUD. METHODS: We used the Nationwide Readmissions Database in 2017 and 2018 in this cohort study. Cancer survivors with an AUD diagnosis during their index hospitalization were included in the exposure group. Propensity score matching was used to identify cancer survivors without AUD for the control group. The primary outcome was all-cause readmission, and secondary outcomes included days to, length of, and total cost of readmission. Outcomes were measured after 90 and 180 days of follow-up. Logistic regression was used to measure the likelihood of readmission, and negative binomial regression and gamma regression were used for the other outcomes. RESULTS: Of 485,962 cancer survivors, 13,953 (2.9%) had co-occurring AUD. Cancer survivors with AUD had slightly higher odds of 90-day (odds ratio, 1.14; 95% CI, 1.06-1.22) and 180-day (odds ratio, 1.11; 95% CI, 1.05-1.18) readmission compared with those without AUD. Cancer survivors with AUD who were readmitted after 90 days also had higher readmission costs ($3,785 vs $3,376; P=.03). No differences in time to and length of readmission were observed between groups. The odds of readmission were higher among cancer survivors with AUD irrespective of age and type of cancer. Male, but not female, cancer survivors with AUD were more likely than those without AUD to be readmitted in both follow-up periods. CONCLUSIONS: This population-based cohort study of cancer survivors in the United States found that AUD is associated with higher 90- and 180-day readmission rates and higher related health care costs after 90 days of follow-up. Hospitalized cancer survivors with AUD may benefit from addiction treatment and discharge planning that addresses their co-occurring AUD.

NaGaPO4F - a KTiOPO4-structured solid sodium-ion conductor.

Advanced ionic conductors are crucial for a large variety of contemporary technologies spanning solid state ion batteries, fuel cells, gas sensors, water desalination, etc. In this work, we report on a new member of KTiOPO4-structured materials, NaGaPO4F, with sodium-ion conductivity. NaGaPO4F has been obtained for the first time via a facile two-step synthesis consisting of a hydrothermal preparation of an ammonia-based precursor, NH4GaPO4F, followed by an ion exchange reaction with NaNO3. Its crystal structure was precisely refined using a combination of synchrotron X-ray powder diffraction and electron diffraction tomography. The material is thermally stable upon 450 °C showing no significant structural transformations or degradation but only a ∼1% cell volume expansion. Na-ion mobility in NaGaPO4F was investigated by a joint experimental and computational approach comprising solid-state nuclear magnetic resonance (NMR) and density functional theory (DFT). DFT and bond-valence site energy (BVSE) calculations reveal 3D diffusion of sodium in the [GaPO4F] framework with migration barriers amounting to 0.22 and 0.44 eV, respectively, while NMR yields 0.3-0.5 eV that, being coupled with a calculated bandgap of ∼4.25 eV, makes NaGaPO4F a promising fast Na-ion conductor.

Synergistic Antimicrobial Effect of Cold Atmospheric Plasma and Redox-Active Nanoparticles.

Cold argon plasma (CAP) and metal oxide nanoparticles are well known antimicrobial agents. In the current study, on an example of Escherichia coli, a series of analyses was performed to assess the antibacterial action of the combination of these agents and to evaluate the possibility of using cerium oxide and cerium fluoride nanoparticles for a combined treatment of bacterial diseases. The joint effect of the combination of cold argon plasma and several metal oxide and fluoride nanoparticles (CeO2, CeF3, WO3) was investigated on a model of E. coli colony growth on agar plates. The mutagenic effect of different CAP and nanoparticle combinations on bacterial DNA was investigated, by means of a blue-white colony assay and RAPD-PCR. The effect on cell wall damage, using atomic force microscopy, was also studied. The results obtained demonstrate that the combination of CAP and redox-active metal oxide nanoparticles (RAMON) effectively inhibits bacterial growth, providing a synergistic antimicrobial effect exceeding that of any of the agents alone. The combination of CAP and CeF3 was shown to be the most effective mutagen against plasmid DNA, and the combination of CAP and WO3 was the most effective against bacterial genomic DNA. The analysis of direct cell wall damage by atomic force microscopy showed the combination of CAP and CeF3 to be the most effective antimicrobial agent. The combination of CAP and redox-active metal oxide or metal fluoride nanoparticles has a strong synergistic antimicrobial effect on bacterial growth, resulting in plasmid and genomic DNA damage and cell wall damage. For the first time, a strong antimicrobial and DNA-damaging effect of CeF3 nanoparticles has been demonstrated.

Influence of the Synthesis Scheme of Nanocrystalline Cerium Oxide and Its Concentration on the Biological Activity of Cells Providing Wound Regeneration.

In the ongoing search for practical uses of rare-earth metal nanoparticles, cerium dioxide nanoparticles (nanoceria) have received special attention. The purpose of this research was to study the biomedical effects of nanocrystalline forms of cerium oxide obtained by different synthesis schemes and to evaluate the effect of different concentrations of nanoceria (from 10-2 to 10-6 M) on cells involved in the regeneration of skin cell structures such as fibroblasts, mesenchymal stem cells, and keratinocytes. Two different methods of nanoceria preparation were investigated: (1) CeO-NPs-1 by precipitation from aqueous solutions of cerium (III) nitrate hexahydrate and citric acid and (2) CeO-NPs-2 by hydrolysis of ammonium hexanitratocerate (IV) under conditions of thermal autoclaving. According to the X-ray diffraction, transmission electron microscopy, and dynamic light scattering data, CeO2-1 consists of individual particles of cerium dioxide (3-5 nm) and their aggregates with diameters of 60-130 nm. CeO2-2 comprises small aggregates of 8-20 nm in diameter, which consist of particles of 2-3 nm in size. Cell cultures of human fibroblasts, human mesenchymal stem cells, and human keratinocytes were cocultured with different concentrations of nanoceria sols (10-2, 10-3, 10-4, 10-5, and 10-6 mol/L). The metabolic activity of all cell types was investigated by MTT test after 48 and 72 h, whereas proliferative activity and cytotoxicity were determined by quantitative cell culture counting and live/dead test. A dependence of biological effects on the method of nanoceria preparation and concentration was revealed. Data were obtained with respect to the optimal concentration of sol to achieve the highest metabolic effect in the used cell cultures. Hypotheses about the mechanisms of the obtained effects and the structure of a fundamentally new medical device for accelerated healing of skin wounds were formulated. The method of nanoceria synthesis and concentration fundamentally and significantly change the biological activity of cell cultures of different types-from suppression to pronounced stimulation. The best biological activity of cell cultures was determined through cocultivation with sols of citrate nanoceria (CeO-NPs-1) at a concentration of 10-3-10-4 M.

Calcein-Modified CeO2 for Intracellular ROS Detection: Mechanisms of Action and Cytotoxicity Analysis In Vitro.

Cerium oxide nanoparticles (CeO2 NPs) are metal-oxide-based nanozymes with unique reactive oxygen species (ROS) scavenging abilities. Here, we studied new CeO2 NPs modified with calcein (CeO2-calcein) as an intracellular ROS inactivation/visualization theranostic agent. The molecular mechanisms of the CeO2-calcein intracellular activity, allowing for the direct monitoring of ROS inactivation in living cells, were studied. CeO2-calcein was taken up by both normal (human mesenchymal stem cells, hMSc) and cancer (human osteosarcoma, MNNG/Hos cell line) cells, and was easily decomposed via endogenous or exogenous ROS, releasing brightly fluorescent calcein, which could be quantitatively detected using fluorescence microscopy. It was shown that the CeO2-calcein has selective cytotoxicity, inducing the death of human osteosarcoma cells and modulating the expression of key genes responsible for cell redox status as well as proliferative and migration activity. Such cerium-based theranostic agents can be used in various biomedical applications.

Hybrid Polyelectrolyte Capsules Loaded with Gadolinium-Doped Cerium Oxide Nanoparticles as a Biocompatible MRI Agent for Theranostic Applications.

Layer-by-layer (LbL) self-assembled polyelectrolyte capsules have demonstrated their unique advantages and capability in drug delivery applications. These ordered micro/nanostructures are also promising candidates as imaging contrast agents for diagnostic and theranostic applications. Magnetic resonance imaging (MRI), one of the most powerful clinical imaging modalities, is moving forward to the molecular imaging field and requires advanced imaging probes. This paper reports on a new design of MRI-visible LbL capsules, loaded with redox-active gadolinium-doped cerium oxide nanoparticles (CeGdO2-x NPs). CeGdO2-x NPs possess an ultrasmall size, high colloidal stability, and pronounced antioxidant properties. A comprehensive analysis of LbL capsules by TEM, SEM, LCSM, and EDX techniques was carried out. The research demonstrated a high level of biocompatibility and cellular uptake efficiency of CeGdO2-x-loaded capsules by cancer (human osteosarcoma and adenocarcinoma) cells and normal (human mesenchymal stem) cells. The LbL-based delivery platform can also be used for other imaging modalities and theranostic applications.

Boron Nanoparticle-Enhanced Proton Therapy for Cancer Treatment.

Proton therapy is one of the promising radiotherapy modalities for the treatment of deep-seated and unresectable tumors, and its efficiency can further be enhanced by using boron-containing substances. Here, we explore the use of elemental boron (B) nanoparticles (NPs) as sensitizers for proton therapy enhancement. Prepared by methods of pulsed laser ablation in water, the used B NPs had a mean size of 50 nm, while a subsequent functionalization of the NPs by polyethylene glycol improved their colloidal stability in buffers. Laser-synthesized B NPs were efficiently absorbed by MNNG/Hos human osteosarcoma cells and did not demonstrate any remarkable toxicity effects up to concentrations of 100 ppm, as followed from the results of the MTT and clonogenic assay tests. Then, we assessed the efficiency of B NPs as sensitizers of cancer cell death under irradiation by a 160.5 MeV proton beam. The irradiation of MNNG/Hos cells at a dose of 3 Gy in the presence of 80 and 100 ppm of B NPs led to a 2- and 2.7-fold decrease in the number of formed cell colonies compared to control samples irradiated in the absence of NPs. The obtained data unambiguously evidenced the effect of a strong proton therapy enhancement mediated by B NPs. We also found that the proton beam irradiation of B NPs leads to the generation of reactive oxygen species (ROS), which evidences a possible involvement of the non-nuclear mechanism of cancer cell death related to oxidative stress. Offering a series of advantages, including a passive targeting option and the possibility of additional theranostic functionalities based on the intrinsic properties of B NPs (e.g., photothermal therapy or neutron boron capture therapy), the proposed concept promises a major advancement in proton beam-based cancer treatment.

Discovery of novel arylpiperazine-based DA/5-HT modulators as potential antipsychotic agents - Design, synthesis, structural studies and pharmacological profiling.

Schizophrenia is a mental disorder with a complex pathomechanism involving many neurotransmitter systems. Among the currently used antipsychotics, classical drugs acting as dopamine D2 receptor antagonists, and drugs of a newer generation, the so-called atypical antipsychotics, can be distinguished. The latter are characterized by a multi-target profile of action, affecting, apart from the D2 receptor, also serotonin receptors, in particular 5-HT2A and 5-HT1A. Such profile of action is considered superior in terms of both efficacy in treating symptoms and safety. In the search for new potential antipsychotics of such atypical receptor profile, an attempt was made to optimize the arylpiperazine based virtual hit, D2AAK3, which in previous studies displayed an affinity for D2, 5-HT1A and 5-HT2A receptors, and showed antipsychotic activity in vivo. In this work, we present the design of D2AAK3 derivatives (1-17), their synthesis, and structural and pharmacological evaluation. The obtained compounds show affinities for the receptors of interest and their efficacy as antagonists/agonists towards them was confirmed in functional assays. For the selected compound 11, detailed structural studies were carried out using molecular modeling and X-ray methods. Additionally, ADMET parameters and in vivo antipsychotic activity, as well as influence on memory and anxiety processes were evaluated in mice, which indicated good therapeutic potential and safety profile of the studied compound.

Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction.

A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17-1.23 µM range, exhibiting low to poor activity for hBChE (IC50 = 4.13-9.70 µM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.